3-aryl-4-hydroxyfuranone compounds and the human and animal health use thereof

ABSTRACT

The present invention provides a compound of formula I and the use thereof for the inhibition of bacterial cell wall biosynthesis and for the therapeutic treatment of bacterial infection or disease in a patient in need thereof. The present invention also provides the use of the formula I compound for the control of ecto- or endoparasites in homeothermic animals.

This application is a divisional of U.S. application Ser. No. 10/915,637, filed Aug. 9, 2004, which claims the benefit under 35 U.S.C. §119(e) to U.S. provisional application No. 60/494,330, filed Aug. 11, 2003, both of which are hereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

In the human pharmaceutical arts, the rapidly developing resistance of known bacterial strains to currently prescribed pharmaceuticals has initiated a vigorous search for new classes of antibacterial agents having alternative modes of action. For example, methicillin resistant S. aureus (MRSA), vancomycin resistant Enterococcus (VRE) and penicillin resistant S. pneumo (PRSP) are bacterial strains which do not respond well to current clinical drug therapies.

Peptidoglycan is an essential cell wall polymer which forms a sacculus around the bacterial cell. The biosynthesis of peptidoglycan provides a unique and selective target for antibacterial activity. Peptidoglycan biosynthesis requires ten specific enzymes to perform as many synthetic transformations. These enzymes include MurA, MurB, MurC, MurD, MurE, MurF, MurG, MraY and the transglycosylase and transpeptidase families of enzymes. Inhibition of any one of these essential enzymes leads to loss of cell shape and integrity followed by bacterial death. This applies to both Gram positive and Gram negative microorganisms (Bugg, T. D. et al., Natural Products Reports 1992 199-215). Of these ten essential enzymes, β-lactam antibiotics inhibit transpeptidases, vancomycin inhibits transglycosylases and fosfomycin inhibits MurA.

In the animal health arts, virtually all commercial and most companion animals are affected by ecto- and endoparasites. The outcome associated with said parasitic infection or infestation in said animals is generally clinical disease and subclinical conditions that decrease performance. Insects, such as Phthiraptera (lice) and Diptera (flies), are among the most economically important ectoparasites in animal production. Insects, such as Siphonáptera (fleas), are highly pesteriferous to companion animals. Helminths, such as Trichostrongylus colubriformis, Haemonchus contortus, or the like, are among the most economically important endoparasites in animal production. Nematodes are highly pesteriferous to companion animals. Ecto- and endoparasitic infections and infestations not only seriously effect the economies of raising livestock for meat, wool, hides and milk, but are also a source of great concern for companion animals. New, economic alternative methods and compositions for the prevention, treatment and control of ecto- or endoparasites in warm-blooded animals are constantly being sought.

Therefore, it is an object of this invention to provide compounds which inhibit the Mur family of enzymes and are useful as antibacterial agents, particularly against resistant strains of bacteria.

It is another object of this invention to provide therapeutic methods and pharmaceutical compositions for the treatment of bacterial infection or disease.

It is also an object of this invention to provide an effective method for the prevention, treatment or control of ecto- or endoparasitic infection or infestation in homeothermic animals.

It is a further object of this invention to provide an ecto- or endoparasiticidal composition suitable for use on animals and humans.

It is a feature of this invention that the compounds provided herein act as effective inhibitors of bacterial cell wall biosynthesis via the Mur enzyme pathway.

Other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I

wherein

-   -   R is H;     -   R₁ is phenyl optionally substituted with one, two or three         halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,         C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or         C₂-C₆alkynyl group each optionally substituted,         -   biphenyl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted,         -   naphthyl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted, or         -   heteroaryl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;     -   R₂ is phenyl optionally substituted with one, two or three         halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,         NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,         C₂-C₆alkenyl, C₂-C₆alkynyl or heteroaryl group each optionally         substituted with the proviso that only one of R₁ or R₂ may be an         optionally substituted phenyl group;         -   biphenyl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;         -   naphthyl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;         -   heteroaryl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl group each             optionally substituted; or         -   C₃-C₆cycloalkyl optionally substituted with one, two or             three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,             NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,             C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each             optionally substituted;     -   R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆,         haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted;     -   R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl,         C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or         heteroaryl group each optionally substituted;     -   R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally         substituted C₁-C₆alkyl group; and     -   R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆,         haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together         with the atom to which they are attached to form an optionally         substituted 5- to 7-membered ring optionally containing one or         two additional heteroatoms selected from N, O or S; or         a stereoisomer thereof, a tautomer thereof or a pharmaceutically         acceptable salt thereof.

The present invention also provides methods and compositions useful for the treatment of a bacterial infection or disease in a patient in need thereof.

The present invention further provides a method for the prevention, amelioration or control of ecto- or endoparasitic infection or infestation in a homeothermic animal which comprises administering to said animal a prophylactically, therapeutically or pharmaceutically effective amount of a compound of formula I

wherein

-   -   R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted;     -   R₁ is phenyl optionally substituted with one, two or three         halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,         C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or         C₂-C₆alkynyl group each optionally substituted,         -   biphenyl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted,         -   naphthyl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted, or         -   heteroaryl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;     -   R₂ is phenyl optionally substituted with one, two or three         halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,         NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,         C₂-C₆alkenyl, C₂-C₆alkynyl or heteroaryl group each optionally         substituted;         -   biphenyl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;         -   naphthyl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;         -   heteroaryl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl group each             optionally substituted; or         -   C₃-C₆cycloalkyl optionally substituted with one, two or             three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,             NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,             C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each             optionally substituted;     -   R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆,         haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted;     -   R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl,         C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or         heteroaryl group each optionally substituted;     -   R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally         substituted C₁-C₆alkyl group; and     -   R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆,         haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together         with the atom to which they are attached to form an optionally         substituted 5- to 7-membered ring optionally containing one or         two additional heteroatoms selected from N, O or S; or         a stereoisomer thereof, a tautomer thereof or a pharmaceutically         acceptable salt thereof.

The present invention further provides an ecto- or endoparasiticidal composition which comprises a pharmaceutically acceptable carrier and an ecto- or endoparasiticidally effective amount of a compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION

Many known antibiotics such as the cephalosporins, the penicillins and vancomycin inhibit the biosynthesis of peptidoglycan, an essential cell wall component of both Gram positive and Gram negative bacteria. These antibiotics inhibit membrane-bound enzymes involved in the crosslinking of the cell wall, i.e., the transpeptidation step. Earlier steps in bacterial cell wall biosynthesis have not been the target of action for current commercial antibiotics, with the exception of fosfomycin. These earlier cytoplasmic steps involve biosynthetic conversions which require the MurA through MurF enzymes. Few inhibitors of the enzymes are known to possess antibacterial activity.

Surprisingly, it has now been found that 3-aryl-4-hydroxyfuranone compounds of formula I inhibit bacteria cell wall biosynthesis via the Mur enzyme pathway. Advantageously, said hydroxyfuranone compounds are effective therapeutic agents against bacterial infection or disease, particularly against infection or disease caused by resistant strains of bacteria. Accordingly, the present invention provides 3-aryl-4-hydroxyfuranone compounds of formula I

wherein

-   -   R is H;     -   R₁ is phenyl optionally substituted with one, two or three         halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,         C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or         C₂-C₆alkynyl group each optionally substituted,         -   biphenyl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted,         -   naphthyl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted, or         -   heteroaryl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;     -   R₂ is phenyl optionally substituted with one, two or three         halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,         NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,         C₂-C₆alkenyl, C₂-C₆alkynyl or heteroaryl group each optionally         substituted with the proviso that only one of R₁ or R₂ may be an         optionally substituted phenyl group;         -   biphenyl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;         -   naphthyl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;         -   heteroaryl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl group each             optionally substituted; or         -   C₃-C₆cycloalkyl optionally substituted with one, two or             three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,             NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,             C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each             optionally substituted;     -   R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆,         haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted;     -   R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl,         C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or         heteroaryl group each optionally substituted;     -   R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally         substituted C₁-C₆alkyl group; and     -   R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆,         haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together         with the atom to which they are attached to form an optionally         substituted 5- to 7-membered ring optionally containing one or         two additional heteroatoms selected from N, O or S; or         a stereoisomer thereof, a tautomer thereof or a pharmaceutically         acceptable salt thereof.

As used in the specification and claims, the term halogen designates Br, Cl, I or F and the term aryl designates a carbocyclic aromatic ring system such as phenyl, naphthyl, anthracenyl or the like, preferably phenyl. The term heteroaryl, as used herein, designates a 5- to 10-membered aromatic ring system containing 1, 2 or 3 heteroatoms, which may be the same or different, selected from N, O or S. Such heteroaryl ring systems include pyrrolyl, azolyl, diazolyl, triazolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolinyl, benzothienyl, benzofuranyl, benzodioxolyl, benzisoxazolyl or the like. The term haloalkyl as used herein designates C_(n)H_(2n+1) group having from one to 2n+1 halogen atoms which may be the same or different and the term haloalkoxy as used herein designates an OC_(n)H_(2n+1) group having from one to 2n+1 halogen atoms which may be the same or different.

In the specification and claims, when the terms C₁-C₆alkyl, C₃-C₁₂cycloalkyl, fluorenyl, aryl or heteroaryl are designated as being optionally substituted, the substituent groups which are optionally present may be one or more of those customarily employed in the development of pharmaceutical compounds or the modification of such compounds to influence their structure/activity, persistence, absorption, stability or other beneficial property. Specific examples of such substituents include halogen atoms, nitro, cyano, thiocyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heteroaryl, cycloheteroalkyl or cycloalkyl groups, preferably halogen atoms, C₁-C₄ alkyl, halo(C₁-C₄)alkyl or halo(C₁-C₄)alkoxy groups.

Typically, 0-3 substituents, preferably 1 or 2, the same or different may be present. When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, more preferably up to 4 carbon atoms.

Pharmaceutically acceptable salts may be any salt formed by a compound of formula I and a pharmaceutically acceptable base such as organic or inorganic bases, e.g. alkali metal salts, (i.e., sodium, lithium, or potassium) alkaline earth metal salts, ammonium salts, alkylammonium salts, dialkylammonium or trialkylammonium salts or the like.

Compounds of the invention may exist as one or more stereoisomers or in enolic tautomeric forms. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. Tautomers include enols or ketones. One skilled in the art will appreciate that one stereoisomer or tautomer may be more active or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or tautomer or when separated from the other stereoisomer(s) or tautomer. Additionally, the skilled artisan knows how to separate, enrich or selectively prepare said stereoisomers or tautomers. Accordingly, the present invention comprises compounds of formula I, the stereoisomers thereof, the tautomers thereof and the pharmaceutically acceptable salts thereof. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active or enantiomerically pure form.

Preferred compounds of the invention are those compounds of formula I wherein R₂ is an optionally substituted biphenyl or naphthyl group. Another group of preferred compounds are those compounds of formula I wherein R₁ is phenyl substituted with one or two halogen or C₁-C₆haloalkyl groups. Further preferred compounds of the invention are those compounds of formula I wherein R₁ is an optionally substituted biphenyl group and R₂ is an optionally substituted phenyl group.

More preferred compounds of the invention are those compounds of formula I wherein R₁ is an optionally substituted phenyl group and R₂ is an optionally substituted biphenyl or naphthyl group. Another group of more preferred compounds are those compounds of formula I wherein R₁ is phenyl substituted with one or two halogen or C₁-C₆haloalkyl groups and R₂ is a biphenyl or naphthyl group optionally substituted with one or two halogen, OR₁₂, COR₁₃, C₁-C₆haloalkyl or C₁-C₆alkyl groups. Further more preferred compounds of the invention are those compounds of formula I wherein R₁ is a biphenyl group substituted with one or two halogen and R₂ is an optionally substituted phenyl group.

Among the preferred compounds of the invention are:

-   (5Z)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)methylene]-3-(3,5-dichlorophenyl)-4-hydroxyfuran-2(5H)-one; -   (5Z)-5-[(3′,4′-dichloro-1,1′-biphenyl-2-yl)methylene]-3-(3,4-dichlorophenyl)-4-hydroxyfuran-2(5H)-one; -   5-[(Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-(3-chlorophenyl)-4-hydroxy-2(5H)-furanone; -   (5E)-5-[2′-chloro-2-methyl-1,1′-biphenyl-4-yl)methylene]-3-(3,5-dichloro-phenyl)-4-hydroxyfuran-2(5H)-one; -   (5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-{[2-methoxy-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methylene}furan-2(5H)-one; -   (5Z)-3-(3,5-dichlorophenyl)-5-[2,2′-dimethyl-1,1′-biphenyl-4-yl)methylene]-4-hydroxyfuran-2(5H)-one; -   5-{[2-chloro-3-(trifluoromethyl)phenyl]methylene}-3-(3-fluoro-4-biphenyl)-4-hydroxyfuran-2(5H)-one; -   3-(3-fluoro-4-biphenyl)-5-{[2-fluoro-5-(trifluoromethyl)phenyl]methylene}-4-hydroxyfuran-2(5H)-one; -   (5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-{[2-methyl-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methylene}furan-2(5H)-one; -   (5Z)-5-[3-(benzyloxy)benzylidene]-3-(3,5-dichlorophenyl)-4-hydroxyfuran-2(5H)-one; -   (5Z)-5-[(2′-acetyl-2-methyl-1,1′-biphenyl-4-yl)methylene]-3-(3,5-dichloro-phenyl)-4-hydroxyfuran-2(5H)-one; -   5-[(Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-(3,4-dichlorophenyl)-4-hydroxy-2(5H)-furanone; -   5-[Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-(3,5-dichlorophenyl)-4-hydroxy-2(5H)-furanone; -   3-(2-fluoro[1,1′-biphenyl]-4-yl)-4-hydroxy-5-{(Z)-[3-(trifluoromethyl)phenyl]-methylidene}furan-2(5H)-one; -   5-[(Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxy-2(5H)-furanone; -   (5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-(1-napthylmethylene)furan-2(5H)-one; -   5-{[2-chloro-5-(trifluoromethyl)phenyl]methylene}-3-(3-fluoro-4-biphenyl)-4-hydroxyfuran-2(5H)-one; -   5-{[2-chloro-5-(trifluoromethyl)phenyl]methylene}-3-(4′-ethoxy-4-biphenyl)-4-hydroxyfuran-2(5H)-one; -   (5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-{(4-methoxy-1-naphthyl)methylene]-furan-2(5H)-one; -   (5Z)-3-(3-chlorophenyl)-4-hydroxy-5-{[2-methyl-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methylene]furan-2(5H)-one; -   (5Z)-5-[(3′-4′-dichloro-1,1′-biphenyl-3-yl)methylene]-3-(3,4-dichlorophenyl)-4-hydroxyfuran-2(5H)-one;     a stereoisomer thereof;     a tautomer thereof; or     a pharmaceutically acceptable salt thereof.

The compounds of the invention may be conveniently prepared using conventional synthetic methods and, if required, standard separation and isolation techniques. For example, compounds of formula I may be prepared by reacting a 3-bromo-4-alkoxy-furanone of formula II with an aldehyde of formula III to give the 5-hydroxyalkyl-furanone of formula IV; dehydrating the formula IV hydroxyalkylfuranone to give the corresponding 5-methylenefuranone of formula V; reacting the formula V compound with a boronic acid derivative of formula VI to give the 3-arylfuranone of formula VII; and hydrolyzing the formula VII compound to the desired 4-hydroxyfuranone of formula I.

Alternatively, the formula II compound may be reacted with tributyl tin chloride to give the compound of formula VII. The formula VII compound may then be sequentially reacted with the aldehyde of formula III and dehydrated to give the compound of formula X; and said formula X compound may be reacted with an aryl halide of formula XI to give the 4-alkoxy compound of formula VII. The formula VII compound may then be hydrolyzed as described hereinabove to give the desired compound of formula I. The reactions are shown in flow diagram I wherein R represents C₁-C₆alkyl, Hal represents Cl, Br or I and DMF designates dimethyl formamide.

Compounds of formula I may also be prepared by reacting the formula II 3-bromo-4-alkoxyfuranone with the boronic acid derivative of formula VI to give the 3-aryl-4-alkoxyfuranone of formula XII and converting said formula XII furanone to the desired compound of formula I in a manner similar to that described hereinabove in flow diagram 1. The reaction is shown in flow diagram II wherein R is C₁-C₆alkyl.

Compounds of formula XII may also be prepared by reacting an aryl acetyl chloride of formula XIII with an ester of glycolic acid to give the compound of formula XIV; cyclizing said formula XIV compound in the presence of a base, such as a metal alkoxide or metal amide, to give the 4-hydroxyfuranone of formula XV; and alkylating the 4-hydroxy group using standard conditions such as Mitsunobu conditions to give the formula XII intermediate. The reaction is shown in flow diagram III wherein R represents C₁-C₆alkyl.

Compounds of formula I may also be prepared by reacting a triphenylphosphine salt of formula XVI with an aldehyde in the presence of freshly prepared sodium ethoxide, as described in J. Chem. Soc. Perkin Trans I, 1567, 1985. The reaction is shown in flow diagram IV wherein Ph represents phenyl.

Compounds of formula I wherein R is other than H may be obtained by treatment of the 4-hydroxy compound of formula I with an amine base in the presence of an anhydride or acid chloride to give the corresponding ester or by treatment of said 4-hydroxy compound of formula I with an inorganic base such as potassium carbonate with in the presence of an alkyl, alkenyl, or benzyl halide to give the corresponding ether.

Advantageously, the formula I hydroxyfuranone compounds of the invention wherein R is H and only one of R₁ and R₂ may be an optionally substituted phenyl group are effective as antibacterial agents. Accordingly, in one embodiment of the invention, there is provided a method for the treatment of a bacterial infection or disease in a patient in need thereof which comprises providing to said patient a pharmacologically effective amount of a compound of formula I.

The term, providing, as used herein with respect to providing a compound or substance embraced by the invention, designates either directly administering such a compound or substance, or administering a prodrug, derivative or analog which forms an equivalent amount of the compound or substance within the body.

Bacterial infections include those infections caused by pathogenic bacteria such as the genera Staphylococcus; Streptococcus; Mycobacterium; Echerichia; Bacillus; Clostridium; Pasteurella; Haemophilus; Bordetella; or Pseudomonas; for example S. aureus, E. Faecalis, E. coli, S. pneumo, Staphylococcus, Enterococcus, or the like and resistant bacteria such as methicillin resistant S. aureus, vancomycin resistant Enteroccocus, penicillin resistant S. pneumo, or the like. Among the bacterial diseases which may be treated by the method of invention are: meningitis, pharyngitis, pertussis, pneumonia, bronchitis, endocarditis, cholecystus, peritonitis, enteritis, enterocolitis, gastroenteritis, urethritis, arthritis, tracheitis, bacteremia, tuberculosis, folliculitis, mastitis, dermatitis, osteomyelitis, or the like.

The antibacterial compound of formula I may be provided to a patient in need thereof by oral, parenteral, intravenous, or topical administration or in any common manner known to be an effective administration of an antibacterial agent.

The pharmacologically effective amount administered in the treatment of a specific bacterial disease may vary according to the specific disease being treated, the size, age and response pattern of the patient, the severity of the disease, the judgment of the attending physician or the like. In general, effective amounts for daily oral administration may be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg.

In actual practice, the formula I compounds of the invention are provided by administering the compound or a precursor thereof in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described hereinabove wherein R is H and only one of R₁ or R₂ may be an optionally substituted phenyl group.

In this embodiment of the invention, solid carriers suitable for use in the pharmaceutical composition of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating agents or encapsulating materials. In powders, the carrier may be a finely divided solid which is in admixture with a finely divided compound of formula I. In tablets, the formula I compound may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Said powders and tablets may contain up to 99% by weight of the formula I compound. Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of the invention. Compounds of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. Said liquid composition may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo-regulators, or the like. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier may also be an oily ester such as ethyl oleate or isopropyl myristate.

Compositions of the invention which are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Inventive compositions suitable for oral administration may be in either liquid or solid composition form.

Ecto- and endoparasiticidal infection and infestation are a constant problem in animal husbandry and in the care and raising of companion animals. Important agronomic and companion animals such as cattle, sheep, horses, goats, pigs, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, minks, chinchillas, raccoons, chickens, geese, turkeys, ducks, dogs, cats or the like are prone to attack and infestation by biting and sucking ectoparasitic insects such as Diptera, Muscidae or Siphonáptera. Helminthiases is a widespread disease found in many farm and companion animals including cattle, sheep, swine, horses, poultry, fish, rabbits, goats, dogs, cats, or the like, as well as in humans. Among the helminths, which cause significant damage are trematodes such as Faciola hepatica or nematodes such as Trichostrongylus colubriformis, Haemonchus contortus and the like. Surprisingly, it has now been found that 3-aryl-4-hydroxyfuranone compounds of formula I wherein R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally substituted, may be used to control, prevent, ameliorate or effectively treat infection and infestation of ectoparasites such as Diptera, Muscidae or Siphonáptera, or endoparasites such as helminths, including nematodes in animals and humans. Advantageously, said hydroxyfuranone compounds may be particularly effective for controlling, preventing or treating infection or infestation of resistant strains of ecto- or endoparasites. Accordingly, in another embodiment of the invention, there is provided a method for the prevention, amelioration or control of ecto- or endoparastic infection or infestation in a homeothermic animal which comprises administering to said animal a prophylactically, therapeutically, or pharmaceutically effective amount of a 3-aryl-4-hydroxyfuranone compound of formula I

wherein

-   -   R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted;     -   R₁ is phenyl optionally substituted with one, two or three         halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,         C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or         C₂-C₆alkynyl group each optionally substituted,         -   biphenyl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted,         -   naphthyl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted, or         -   heteroaryl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;     -   R₂ is phenyl optionally substituted with one, two or three         halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,         NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,         C₂-C₆alkenyl, C₂-C₆alkynyl or heteroaryl group each optionally         substituted;         -   biphenyl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;         -   naphthyl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;         -   heteroaryl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl group each             optionally substituted; or         -   C₃-C₆cycloalkyl optionally substituted with one, two or             three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,             NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,             C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each             optionally substituted;     -   R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆,         haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted;     -   R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl,         C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or         heteroaryl group each optionally substituted;     -   R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally         substituted C₁-C₆alkyl group; and     -   R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆,         haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together         with the atom to which they are attached to form an optionally         substituted 5- to 7-membered ring optionally containing one or         two additional heteroatoms selected from N, O or S; or         a stereoisomer thereof, a tautomer thereof or a pharmaceutically         acceptable salt thereof.

Preferred compounds of formula I useful in the animal health method of invention are those compounds of formula I wherein R₂ is phenyl substituted with one or two halogen, C₁-C₆haloalkyl or cyano groups. Also preferred are those compounds of formula I wherein R₂ is an optionally substituted biphenyl group. Another group of preferred compounds useful in the animal health method of the invention are those compounds of formula I wherein R₁ is phenyl substituted with one or two halogen, C₁-C₆haloalkyl or cyano groups. Further preferred compounds are those compounds of formula I wherein R₁ is an optionally substituted biphenyl group.

Among the preferred compounds of formula I useful in the animal health method of invention are:

-   5-(4-fluorobenzylidene)-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-one; -   5-(4-fluorobenzylidene-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one; -   5-(4-fluorobenzylidene-3-(4-trifluoromethylphenyl)-4-hydroxyfuran-2(5H)-one; -   5-(4-cyanobenzylidene-3-(4-trifluoromethylphenyl)-4-hydroxyfuran-2(5H)-one; -   5-(4-trifluoromethylbenzylidene-3-(4-trifluoromethylphenyl)-4-hydroxyfuran-2(5H)-one; -   5-(4-chlorobenzylidene-3-(4-trifluoromethylphenyl)-4-hydroxyfuran-2(5H)-one; -   5-(4′-cyanobiphenyl-4-ylmethylene)-3-(4-trifluoromethylphenyl)-4-hydroxyfuran-2(5H)-one; -   5-(4-cyanobenzylidene)-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-one; -   (5Z)-(4′-cyanobiphenyl-4-ylmethylene)-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-one; -   5-(4′-chlorobiphenyl-4-ylmethylene)-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one; -   5-(4-cyanobenzylidene)-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one; -   5-(4-chlorobenzylidene)-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-one; -   (5E)-(4′-cyanobiphenyl-4-ylmethylene)-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one; -   (5Z)-(2-trifluoromethylbenzylidene)-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one; -   (5Z)-(4-chlorobenzylidene)-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-one; -   (5Z)-(1,1′-biphenyl]-4-ylmethylidene-3-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxyfuran-2(5H)-one; -   (5Z)-(1,1′-biphenyl]-4-ylmethylidene-3-[3,5-bis(chloro)phenyl]-4-hydroxyfuran-2(5H)-one; -   (5Z)-(4′-chlorobiphenyl-4-ylmethylene)-3-(4-chlorophenyl)-4-hydroxyfuran-2(5H)-one; -   (5Z)-(4′-cyanobiphenyl-4-ylmethylene)-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one; -   Acetic acid     4-(4-chlorophenyl)-2-(4-cyanobenzylidene)-5-oxo-2,5-dihydrofuran-3-yl-ester; -   2,2 Dimethylpropionic acid     4-(4-chlorophenyl)-2-(4-cyanobenzylidene)-5-oxo-2,5-dihydrofuran-3-yl-ester;     a stereoisomer thereof;     a tautomer thereof; or     a pharmaceutically acceptable salt thereof.

Ectoparasitic insects which may be controlled, ameliorated or treated by the animal health method of invention include Diptera, Muscidae or Siphonáptera, in particular, Diptera: Muscidae such as Musca autumnalis (face flies), Haemtobia irritans (horn flies) Stomoxys calcitrans (stable flies), heel flies, tsetse flies, blow flies or the like. Said insects are breeders of filth and vectors of disease and are serious ectoparasitic pests of important agronomic animals such as cattle, horses and sheep. Further, Diptera: Hippoboscidae (louse flies) such as Melophagus ovinus (sheep ked), which is a serious parasite of sheep are problematic in animal production.

Among the Phthiraptera families known to be ectoparasites of animals are: Trichodectidae such as Bovicola bovis (important cattle-biting louse), B. ovis (sheep-biting louse) or B. equi (horsebiting louse); Haematopinidae such as Haematopinus suis (hog louse), or H. asini (horse sucking louse); Linognathidae such as Linognathus stenopsis (goat sucking louse) or L. vitali (long-nosed cattle louse); or the like.

One of the Siphonáptera families known to infest companion animals is Pulicìdae such as Archaeopsyllnìae (cat and dog fleas), Spilopsyllìnae (rabbit fleas), or the like.

Endoparasitic infections which may be controlled, ameliorated or treated by the method of the invention include those Helminthiases infections caused by the class Trematoda, commonly known as flukes or flatworms or by the class Nematoda, commonly known as nematodes or roundworms. The method of the invention is particularly effective against infection caused by Trematoda, especially members of the genera Fasciola, Fascioloides, Paramphistomum, Dicrocoelium, Eurytrema, Ophisthorchis, Fascioiopsis, Echinostoma, or Paragonimus. The method of the invention is uniquely effective against trematodes and may provide significant control of the economically important Faciola hepatica, commonly known as liver fluke. Helminthiases infection is also caused by a group of worms referred to as nematodes. Nematodes cause serious damage to the walls and tissues of the organs in which they reside, including the intestinal tract, heart, lungs and blood vessels, and are a primary cause of anemia. If left untreated they may result in death to the infected host. The nematodes most commonly found to be the infecting agents of warm-blooded animals include Haemonchus, Ostertagia, Cooperia, Drofilaria, Oesphagastomum, Nematodirus and Dictyocaulus.

In addition to helmintic infection, the present method of invention is also useful for the control of endoparasitic arthropod infestations such as cattle grub. The method of invention is also effective against infection caused by nematodes such as, T. colubriformis, H. contortus, or the like.

Homeothermic animals suitable for use in the method of invention are all warm-blooded animals susceptible to ecto- or endoparasitic infection or infestation including farm animals such as cattle, sheep, swine, horses, poultry, rabbits, goats, or the like, preferably cattle, sheep, swine or horses; companion animals such as dogs, cats, gerbils, rabbits, birds or the like, preferably dogs or cats; or humans.

The effective amount of the formula I compound to be used in the animal health method of invention will vary according to the specific compound used, the mode of application used, the identity of the parasite to be controlled, the degree of infection or infestation, the extent of the parasite population, the nature of the target host, the weather conditions or the like. Effective dosages may range from 0.1 mg/kg to 100 mg/kg, preferably about 1.0 mg/kg to 50 mg/kg. Naturally, quantities of greater than effective amounts of said formula I compound may be administered, but are not required for the protection of the target animals from the ecto- or endoparasite.

Compounds of formula I may be administered to the target homeothermic animal orally, topically or parenterally, preferably orally. For example, the formula I 3-aryl-4-hydroxyfuranone compound may be administered to said animal in or with their drinking water or as a feed additive or in the form of a pill, tablet, bolus, implant, capsule or drench. The formula I compound may also be administered topically by applying said compound to the skin, hide or hair of the homeothermic animal. Parenteral administration, i.e., intramural, intramuscular or subcutaneous injection is also suitable for the inventive method.

In actual practice, the compounds of formula I are provided by administering the compound or a precursor thereof in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present invention provides an ecto- or endoparasiticidal composition which comprises a pharmaceutically acceptable carrier and an effective amount of a 3-aryl-4-hydroxyfuranone compound of formula I

wherein

-   -   R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted;     -   R₁ is phenyl optionally substituted with one, two or three         halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,         C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or         C₂-C₆alkynyl group each optionally substituted,         -   biphenyl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted,         -   naphthyl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted, or         -   heteroaryl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;     -   R₂ is phenyl optionally substituted with one, two or three         halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,         NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,         C₂-C₆alkenyl, C₂-C₆alkynyl or heteroaryl group each optionally         substituted;         -   biphenyl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;         -   naphthyl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;         -   heteroaryl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl group each             optionally substituted; or         -   C₃-C₆cycloalkyl optionally substituted with one, two or             three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,             NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,             C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each             optionally substituted;     -   R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆,         haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted;     -   R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl,         C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or         heteroaryl group each optionally substituted;     -   R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally         substituted C₁-C₆alkyl group; and     -   R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆,         haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together         with the atom to which they are attached to form an optionally         substituted 5- to 7-membered ring optionally containing one or         two additional heteroatoms selected from N, O or S; or         a stereoisomer thereof, a tautomer thereof or a pharmaceutically         acceptable salt thereof.

In this embodiment of the invention, solid carriers suitable for use in the ecto- or endoparasiticidal composition of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating agents or encapsulating materials. In powders, the carrier may be a finely divided solid which is in admixture with a finely divided compound of formula I. In tablets, the formula I compound may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Said powders and tablets may contain up to 99% by weight of the formula I compound. Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of the invention. Compounds of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. Said liquid composition may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo-regulators, or the like. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), dimethyl sulfoxide, alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier may also be an oily ester such as ethyl oleate or isopropyl myristate.

Ecto- or endoparasiticidal compositions of the invention which are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Inventive compositions suitable for oral administration may be in either liquid or solid composition form.

An ecto- or endoparasiticidal composition of the invention may be in the form of a pill, tablet, bolus, implant, capsule or drench, containing sufficient formula I compound to provide the treated animal with about 0.01 mg/kg to 100 mg/kg of animal body weight per day of the formula I compound. These dosage forms are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, fillers, disintegrating agents and/or builders such as starch, lactose, talc, magnesium stearate, vegetable gums or the like. These unit dosage formulations may be varied according to the kind and size of the animal to be treated, the severity or type of infection encountered, the weight of the host animal, or the like.

For a parenteral composition, the formula I compound may be dispersed in a physiologically acceptable solvent for subcutaneous injection or it may be dispersed in a fat or wax or mixture thereof containing an oil, buffer, surfactant, stabilizer, preservative and salt. Components useful in these preparations include carbowax, aluminum monostearate gel, diethyl succinate, soya oil, glyercal dioleate, saline and capric/caprylic triglycerides.

The formula I compound may also be applied topically to the larger animals such as swine, sheep, cattle and horses and companion animals such as dogs and cats in the form of aqueous dips or sprays. For this inventive composition, the active compound is generally prepared as a wettable powder, emulsifiable concentrate, aqueous flowable or the like, which is mixed with water at the site of treatment and applied topically to the hide, skin or hair of the animal. Such sprays or dips usually contain about 0.5 ppm to 5000 ppm and preferably about 1 ppm to 3000 ppm of the compound.

Advantageously, the formula I compound may also be prepared as a pour-on formulation and poured on the backs of the animals such as swine, cattle, sheep, horses, poultry and companion animals. Such pour-on compositions are generally prepared by dissolving, dispersing or emulsifying the formula I compound in a suitable nontoxic pharmacologically acceptable diluent for pour-on and administration. The diluent must be compatible with the compound and should not be a source of irritation or damage to the animals hide, skin or hair. Such diluents include vegetable oils, spreading oils, polyhydric alcohols, aliphatic or aromatic hydrocarbons, esters of fatty acids and lower alkyl ketones.

A typical pour-on formulation includes about 0.5% to 30% by weight of the formula I compound, about 30% to 60% by weight of an aliphatic or aromatic hydrocarbon, mono or polyhydric alcohol, lower alkyl ketone or mixtures thereof 0 to about 20% by weight of a vegetable or mineral oil and about 0.5% to 30% by weight of a spreading oil. Another typical pour-on contains about 45% by weight of xylene about 15% by weight of the formula I hydroxy furanone compound, about 10% by weight of corn oil or mineral oil, about 25% by weight of cyclohexanone and about 5% by weight of other pharmacologically acceptable spreading agents, antifoam agents, surfactants or the like.

Surprisingly, the formula I compounds of the invention wherein R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally substituted, are useful for the control of plant parasitic nematodes and nematodes living freely in soil. Accordingly, in a further embodiment of the invention, there is provided a method for the control of nematode pests or parasites which comprises contacting said pests or parasites, their food supply, habitat or breeding ground with a pesticidally or parasiticidally effective amount of a compound of formula I

wherein

-   -   R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted;     -   R₁ is phenyl optionally substituted with one, two or three         halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,         C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or         C₂-C₆alkynyl group each optionally substituted,         -   biphenyl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted,         -   naphthyl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted, or         -   heteroaryl optionally substituted with one, two or three             halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁,             C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;     -   R₂ is phenyl optionally substituted with one, two or three         halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,         NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,         C₂-C₆alkenyl, C₂-C₆alkynyl or heteroaryl group each optionally         substituted;         -   biphenyl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;         -   naphthyl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally             substituted;         -   heteroaryl optionally substituted with one, two or three             halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈,             NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl,             C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl or heteroaryl group each             optionally substituted; or         -   C₃-C₆cycloalkyl optionally substituted with one, two or             three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆,             NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl,             C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each             optionally substituted;     -   R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆,         haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted;     -   R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl,         C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or         heteroaryl group each optionally substituted;     -   R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally         substituted C₁-C₆alkyl group; and     -   R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆,         haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl,         C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally         substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together         with the atom to which they are attached to form an optionally         substituted 5- to 7-membered ring optionally containing one or         two additional heteroatoms selected from N, O or S; or         a stereoisomer thereof, a tautomer thereof or a pharmaceutically         acceptable salt thereof.

Plant parasitic nematodes include, but are not limited to, ectoparasites such as Xiphinema spp., Longidorus spp. and Trichodorus spp.; semi-parasites such as Tylenchulus spp.; migratory endoparasites such as Pratylenchus spp., Radopholus spp. or Scutellonema spp.; sedentary parasites such as Heterodera spp., Globodera spp. and Meloidogyne spp.; and stem and leaf endoparasites such as Ditylenchus sppp., Aphelenchoides spp. or Hirshmaniella spp.

In agronomic practice, generally about 0.1 ppm to 10,000 ppm, preferably about 1.0 ppm to 5,000 ppm, of a formula I compound dispersed in water or another liquid carrier, is effective when applied to plants or the soil or water in which the plants are growing or are to be grown to protect the plants from nematode attack or infestation. In this embodiment of the invention the compounds of formula I may be formulated as an emulsifiable concentrate, flowable concentrate, wettable powder, dilute spray, dry compacted granule, dust, suspension concentrate, microemulsion or any agronomic pesticidal composition which lends itself to seed, soil, water or foliage application and provides the requisite nematode control and plant protection.

Accordingly, in this further embodiment of the invention, there is provided a method for the protection of a growing or harvested plant from attack or infestation by nematode pests or parasites which comprises applying to the foliage of said plant or to the soil or water in which it is growing a pesticidally effective amount of a compound of formula I as described hereinabove and wherein R is H, COR₄ or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally substituted.

When applied to the foliage of plants or to the soil or water in which the plants are growing or are to be grown, effective amounts may be that amount sufficient to provide about 0.1 kg/ha to 4.0 kg/ha of a compound of formula I.

For a more clear understanding, and in order to illustrate the invention more clearly, specific examples thereof are set forth hereinbelow. The following examples are merely illustrative and are not to be understood as limiting the scope and underlying principles of the invention in any way.

Unless otherwise stated, all parts are parts by weight. The term NMR designates nuclear magnetic resonance. The terms THF and EtOAc designate tetrahydrofuran and ethyl acetate, respectively. The term DMF designates dimethyl formamide and the term DMSO designates dimethylsulfoxide.

EXAMPLES Example 1 Preparation of 3-Bromo-5-(hydroxynaphthalen-1-ylmethyl)-4-methoxy-5H-furan-2-one

A solution of N-isopropylcyclohexylamine (3.62 g, 4.22 mL, 28.22 mmol) in THF at −78° C. is treated with n-butyl lithium (2.1M in hexane, 13.2 L), and stirred at −78° C. for 0.5 h. The resultant suspension is added dropwise to a suspension of 3-bromo-4-methoxy-5H-furan-2-one (4.95 g, 25.65 mmol) in THF at −78° C. The reaction mixture is stirred at −78° C. for 0.75 h, treated dropwise with a solution of 1-naphthylcarboxaldehyde (4.0 g, 25.65 mmol) in THF, stirred for 0.5 h at −78° C., allowed to warm to 0° C., quenched with saturated NH₄Cl and extracted with EtOAc. The extracts are combined, dried over MgSO₄ and concentrated in vacuo. The resultant red oil residue is passed through a pad of silica gel using 100% hexanes and 80% EtOAc in hexanes as eluents to afford the title product as a yellow foam, 5.3 g (59% yield), identified by NMR and mass spectral analyses.

Example 2 Preparation of 3-Bromo-4-methoxy-5-[(Z)-1-naphthylmethylidene]furan-2(5H)-one

A solution of 3-bromo-5-(hydroxynaphthalen-1-ylmethyl)-4-methoxy-5H-furan-2-one (5.3 g, 15.17 mmol) and triethylamine (9.22 g, 12.7 mL, 91.1 mmol) in anhydrous CH₂Cl₂ at 0° C. is treated dropwise with methane sulfonyl chloride (6.96 g, 4.7 mL, 60.7 mmol), stirred for 0.5 h at 0° C., allowed to warm to room temperature, treated sequentially with additional triethylamine (4.64 g, 6.4 mL, 45.9 mmol) and methane sulfonyl chloride (3.55 g, 2.4 mL, 31 mmol), stirred until the disappearance of starting material and diluted with EtOAc and water. The phases are separated and the organic phase is dried over Na₂SO₄ and concentrated in vacuo. The resultant residue is flash chromatographed (silica gel, 25% EtOAc in hexanes as eluent) to afford the title product as a yellow solid, 4.0 g (80% yield), mp 143-1481° C., identified by NMR and mass spectral analyses.

Example 3 Preparation of 3-(4-Chlorophenyl)-4-methoxy-5-[(Z)-1-naphthylmethyl-idene]furan-2(5H)-one

A stirred mixture of 4-chlorophenylboronic acid (259 mg, 166 mmol), K₃PO₄ (962 mg, 4.53 mmol) and Pd(PPh₃)₄ (52 mg, 45.3 μmol) under N₂ is treated sequentially with of 3-bromo-4-methoxy-5-[(Z)-1-naphthylmethylidene]furan-2(5H)-one (500 mg, 1.51 mmol) and 9.3 mL of a 2:1 v/v mixture of dioxane/THF, heated at 90° C. until the disappearance of starting material by thin layer chromatography, cooled to room temperature, diluted with water and extracted with EtOAc. The extracts are combined, dried over MgSO₄ and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, 25% EtOAc in hexanes as eluent) to afford the title product as a yellow solid, 380 mg (69% yield), identified by NMR and mass spectral analyses.

Example 4 Preparation of 3-(4-Chlorophenyl)-4-hydroxy-5-[(Z)-1-naphthylmethylidene]-furan-2-(5H)-one

A stirred mixture of 3-(4-chlorophenyl)-4-methoxy-5-[(Z)-1-naphthylmethyl-idene]furan-2(5H)-one (380 mg, 0.998 mmol) and LiBr (86.6 mg, 0.998 mmol) in DMF is heated at 150° C. for 10 min., cooled to room temperature, poured into 5 mL H₂SO₄, diluted with water and extracted with EtOAc. The extracts are combined, washed with water, dried over Na₂SO₄ and concentrated in vacuo. The resultant oil residue is passed through a silica gel pad, using a gradient elution of 100% EtOAc to 9:1 EtOAc:2.5% acetic acid in methanol, to afford the title product as a rust-yellow solid, 270 mg (78% yield), mp 220°-224° C., identified by NMR and mass spectral analyses.

Examples 5-96 Preparation of 3-Aryl-4-hydroxyfuranone Derivatives

Using essentially the same procedures described in Examples 1-4 and employing a suitable arylcarboxaldehyde and the appropriate boronic acid derivative, the compounds shown on Table I are obtained and identified by NMR and mass spectral analyses. Unless otherwise noted, all compounds on Table I are the Z isomer.

TABLE I

Ex. mp No. R₁ R₂ ° C.  5 3-CF₃—C₆H₄ 1-naphthyl 100 (dec)  6 4-CH₃O—C₆H₄ 1-naphthyl 218-222  7 4-CH₃O—C₆H₄ 2-naphthyl   257-258.5  8 3-CF₃—C₆H₄ 2-naphthyl   239-240.8  9 4-CH₃O—C₆H₄ 4-biphenyl 266-269 10 3-CF₃—C₆H₄ 4-biphenyl   240-241.5 11 3-CF₃—C₆H₄ 4-biphenyl^(a) 230 12 3-CF₃—C₆H₄ 5-methylthien-2-yl 249-251 13 4-Cl—C₆H₄ 5-methylthien-2-yl^(a) 257 (dec) 14 4-Cl—C₆H₄ 5-methylthien-2-yl^(b) 256-258 15 4-Cl—C₆H₄ cyclohexyl 200-205 16 3-CF₃—C₆H₄ cyclohexyl^(c) 185-192 17 3-CF₃—C₆H₄ cyclohexyl   170-173.5 18 3-Cl—C₆H₄ 4-(2′-Cl—2CH₃O-biphenyl) 212-215 19 3,5-diCl—C₆H₃ 4-(2,2′-diCH₃O-biphenyl) 202-205 20 3,4-diCl—C₆H₃ 4-(2,2′-diCH₃O-biphenyl) 221-223 21 3,5-diCl—C₆H₃ 4-(2′-Cl-2-CH₃O-biphenyl) 223-225 22 3-Cl—C₆H₄ 4-(2-CH₃O-2′-CH₃- 176-180 biphenyl) 23 3-Cl—C₆H₄ 4-(2′-CH₃O-2-CH₃- 223-224 biphenyl) 24 3,5-diCl—C₆H₃ 4-(2′-CH₃O-2-CH₃- 215-219 biphenyl) 25 3,5-diCl—C₆H₃ 4-(2-CH₃O-2′-CH₃- 140-150 biphenyl) 26 3-Cl—C₆H₄ 4-(2-CH₃-2′-CF₃-biphenyl) 218-222 27 3,5-diCl—C₆H₃ 4-(2-CH₃-2′-CF₃-biphenyl) 223-228 28 3-Cl—C₆H₄ 4-(2,2′-di-CH₃-biphenyl) 219-222 29 3,5-diCl—C₆H₃ 4-(2,2′-di-CH₃-biphenyl) 228-231 30 3-Cl—C₆H₄ 4-(2′-Cl-2-CH₃-biphenyl) 211-215 (dec) 31 3,5-diCl—C₆H₃ 4-(2′-Cl-2-CH₃-biphenyl)^(c) 230-235 32 3-Cl—C₆H₄ 4-(2-CH₃O-2′-CF₃- 219-222 biphenyl) 33 3,5-diCl—C₆H₃ 4-(2-CH₃O-2′-CF₃- 219-222 biphenyl) 34 3,5-diCl—C₆H₃ 4-[3-F-(4-morpholin-4- 262-265 yl)phenyl] 35 3-Cl—C₆H₄ 1-(4-methoxynaphthyl)^(d) 233 (dec) 36 3,5-di-Cl—C₆H₃ 1-(4-methoxynaphthyl) 276-278 37 3-Cl—C₆H₄ 1-[(4-morpholin-4- 239-241 yl)naphthyl] 38 3,5-diCl—C₆H₃ 1-[(4-morpholin-4- 253-256 yl)naphthyl] 39 3,5-diCl—C₆H₃ 4-(2-CH₃-2′CH₃SO₃- 221-229 biphenyl) 40 3,5-diCl—C₆H₃ 4-(2′-CH₃CO-2-CH₃- 223-225 biphenyl) 41 2-naphthyl 5-methylthien-2-yl 144-145 (dec) 42 2-naphthyl 3-CF₃—C₆H₄ 185-189 43 2-naphthyl 4-Cl—C₆H₄ 243-250 44 2-naphthyl 1-naphthyl 205-207 45 2-naphthyl 4-biphenyl 200-203 (dec) 46 1-naphthyl 4-Cl—C₆H₄ 235-237 47 1-naphthyl 1-naphthyl 216-218 48 1-naphthyl 3-CF₃—C₆H₄ 173-176 49 1-naphthyl 3-CF₃—C₆H₄ ^(e) 224-226 50 1-naphthyl 4-biphenyl 249-253 51 2-naphthyl Cyclohexyl 205-208 52 2-naphthyl 2-naphthyl 285-290 53 4-Cl—C₆H₄ 4-biphenyl 282-285 54 4-Cl—C₆H₄ 2-naphthyl 284-286 55 3-CF₃—C₆H₄ 4-(3′-CF₃-biphenyl) 220-225 56 1-naphthyl 2-naphthyl 235-237 57 4-CH₃—C₆H₄ 4-(4′-CH₃-biphenyl) 261-265 58 2-F—C₆H₄ 4-(2′-F-biphenyl) 234-236 59 2-CN—C₆H₄ 4-(3′-CN-biphenyl) 259-263 60 2-CH₃—C₆H₄ 4-(2′-CH₃-biphenyl) 164-167 61 2-CF₃—C₆H₄ 4-(2′-CF₃-biphenyl) 210-213 62 4-CN—C₆H₄ 4-(4′-CN-biphenyl) 238-240 63 3,5-di-Cl—C₆H₃ 4-(3′,5′-di-Cl-biphenyl) 236-240 64 4-Cl—C₆H₄ 4-(4′-Cl-biphenyl) 276-280 65 2,4-di-Cl—C₆H₄ 4-biphenyl 252-256 66 3,4-di-Cl—C₆H₄ 4-biphenyl 265-269 67 3,5-di-Cl—C₆H₃ 4-biphenyl 279-280 68 3,5-di-Cl—C₆H₃ 4-biphenyl 232-235 69 3-Cl—C₆H₄ 4-biphenyl 248-250 70 3,5-di-Cl—C₆H₃ 1-naphthyl 244-245 71 4-CF₃—C₆H₄ 1-naphthyl 245-247 72 3-CH₃O—C₆H₄ 1-naphthyl 214-216 73 4-[(1Z)CNOH—C₆H₄] 1-naphthyl^(f) 209-211 74 4-CO₂CH₃—C₆H₄ 1-naphthyl 242-244 75 3-CO₂C₂H₅—C₆H₄ 1-naphthyl^(g) 169-171 76 3-CHO—C₆H₄ 1-naphthyl 220-221 77 3-CNOH—C₆H₄ 1-naphthyl 213-215 78 4-Cl—C₆H₄ 1-[(4- 228 dimethylamino)naphthyl] 79 3,5-di-Cl—C₆H₃ 1-[(4- 168-194 dimethylamino)naphthyl] 80 3,5-di-Cl—C₆H₃ 1-[(4- 167-172 dimethylamino)naphthyl]^(h) 81 4-CF₃—C₆H₄ 1-[(4- 234-237 dimethylamino)naphthyl] 82 3-CF₃—C₆H₄ 3-CF₃—C₆H₄ 221-224 83 4-Cl—C₆H₄ 3-CF₃—C₆H₄ 216-220 84 4-CH₃O—C₆H₄ 3-CF₃—C₆H₄ 200-226 (dec) 85 4-Cl—C₆H₄ 4-Cl—C₆H₄ 261-264 86 3-CF₃—C₆H₄ 4-Cl—C₆H₄ 233-236 87 4-CH₃O—C₆H₄ 4-Cl—C₆H₄ 272-275 88 4-CH₃O—C₆H₄ 4-CH₃O—C₆H₄ 245 89 4-CH₃O—C₆H₄ 4-CH₃O—C₆H₄ ^(a) 163-167 90 3-CF₃—C₆H₄ 4-CH₃O—C₆H₄ 221-225 91 3,5-diCl—C₆H₃ 4-[3-F-(4-piperizin-4-yl-1- 246-249 ethylcarboxylate)phenyl] 92 3-Cl—C₆H₄ 4-[3-F-(4-piperizin-4-yl-1- 226-228 ethylcarboxylate)phenyl] 93 3,5-diCl—C₆H₃ 3-(benzyloxy)phenyl 198-200 94 3,5-diCl—C₆H₃ 2-(benzyloxy)phenyl — 95 3,5-diCl—C₆H₃ 4-{3-Cl-[4-(2- 259-261 Cl—C₆H₄)piperazin-1- yl]phenyl} 96 3,5-diCl—C₆H₃ 3-{[(2R)2- 226 methylcarboxylate]- piperidinyl-1- carbonyl}phenyl ^(a)4.25:1 E:Z isomer mixture ^(b)3.5:1 Z:E isomer mixture ^(c)E isomer ^(d)3:1 Z:E isomer mixture ^(e)7.1 E:Z isomer mixture ^(f)1:1.55 E:Z isomer mixture ^(g)E Z isomer mixture ^(h)1:1 E:Z isomer mixture

Example 97 Preparation of 5-{Hydroxy-[2-(trifluoromethyl)phenyl]methyl}-4-methoxy-5H-furan-2-one

A mixture of 4-methoxy-5H-furan-2-one (2.00 g, 17.5 mmol), 2-(trifluoromethyl)-benzaldehyde (3.05 g, 17.5 mmol) and lithium hydroxide monohydrate (0.148 g, 3.53 mmol) in acetonitrile is stirred at room temperature for 0.5 h, treated with water, stirred for 0.5 h and concentrated in vacuo. The resultant residue is diluted with water and filtered. The filtercake is dried in vacuo to give the title product as a white solid, 3.00 g (59% yield), mp 126-128° C., identified by NMR and mass spectral analyses.

Example 98 Preparation of 3-Bromo-4-methoxy-5-{(Z)-[2-(trifluoromethyl)benzylidene]}-5H-furan-2-one

A stirred solution of 5-{hydroxy-[2-(trifluoromethyl)phenyl]methyl}-4-methoxy-5H-furan-2-one (2.9 g, 10.1 mmol) in acetonitrile at room temperature is treated dropwise with bromine (0.52 ml, 10.1 mmol), stirred for 24 h and concentrated in vacuo. The resultant residue is diluted with CH₂Cl₂ and triethylamine (4.25 ml), cooled in an ice bath, treated with methane sulfonyl chloride (1.6 ml), stirred for 0.5 h at ice bath temperatures, allowed to warm to room temperature for 2 h and diluted with EtOAc and water. The organic phase is separated, dried over MgSO₄ and concentrated in vacuo. This residue is flash chromatographed (SiO₂, hexane/EtOAc as eluent) to afford the title product as a white solid, 0.20 g (6% yield), mp 136-138° C., identified by NMR and mass spectral analyses.

Example 99 Preparation of 3-[1,1′-Biphenyl]-4-yl-4-hydroxy-5-{(Z)-[2-(trifluoromethyl)benzylidene]}-5H-furan-2-one

Using essentially the same procedures described in Examples 3 and 4 hereinabove and employing the 3-bromofuranone of Example 83 and 4-biphenylboronic acid as reagents, the title product is obtained as white solid, mp 228-230° C., identified by NMR and mass spectral analyses.

Examples 100-162 Preparation of 3-Aryl-4-hydroxyfuranone Derivatives

Using essentially the same procedures described in Examples 1-4 and 82-84 and employing a suitable arylcarboxaldehyde and appropriate boronic acid derivative, the compounds shown on Table II are obtained and identified by NMR and mass spectral analyses. Unless otherwise noted, all compounds on Table II are the Z isomer.

TABLE II

Ex. mp No. R₁ R₂ ° C. 100 4-biphenyl cyclohexyl 204-207 101 4-biphenyl 3-pyridyl 252-255 102 4-biphenyl 1-naphthyl 226-230 103 4-biphenyl 2-naphthyl 266-270 104 4-biphenyl 5-methylthien-2-yl 235-240 105 4-biphenyl 4-CF₃—C₆H₄ 250-255 106 4-(2-F-biphenyl) 3-CF₃—C₆H₄ 222-226 107 4-(2-F-biphenyl) 2-CF₃—C₆H₄ 224-228 108 3-biphenyl 3-CF₃—C₆H₄ 210-212 109 3-biphenyl 3-F-5-CF₃—C₆H₃ — 110 4-(2-F-biphenyl) 3-F-5-CF₃—C₆H₃ — 111 4-(4′-propylbiphenyl) 3-F-5-CF₃—C₆H₃ — 112 3-biphenyl 3-F-5-CF₃—C₆H₃ — 113 4-biphenyl 2-Cl-3-CF₃—C₆H₃ — 114 4-(2-F-biphenyl) 2-Cl-3-CF₃—C₆H₃ — 115 4-(4′-propylbiphenyl) 2-Cl-3-CF₃—C₆H₃ — 116 4-(4′-t-butylbiphenyl) 2-Cl-3-CF₃—C₆H₃ — 117 4-(4′-C₂H₅O-biphenyl) 2-Cl-3-CF₃—C₆H₃ — 118 4-biphenyl 2-F-5-CF₃—C₆H₃ — 119 4-(2-F-biphenyl) 2-F-5-CF₃—C₆H₃ — 120 4-(4′-t-butylbiphenyl) 2-F-5-CF₃—C₆H₃ — 121 3-biphenyl 2-F-5-CF₃—C₆H₃ — 122 4-(4′-C₂H₅O-biphenyl 2-F-5-CF₃—C₆H₃ — 123 4-(4′-t-butylbiphenyl) 4-Cl-3-CF₃—C₆H₃ — 124 4-(4′-C₂H₅O-biphenyl) 4-Cl-3-CF₃—C₆H₃ — 125 4-biphenyl 2-Cl-5-CF₃—C₆H₃ — 126 4-(2-F-biphenyl) 2-Cl-5-CF₃—C₆H₃ — 127 4-(4′-propylbiphenyl) 2-Cl-5-CF₃—C₆H₃ — 128 4-(4′-t-butylbiphenyl) 2-Cl-5-CF₃—C₆H₃ — 129 4-(4′-C₂H₅O-biphenyl) 2-Cl-5-CF₃—C₆H₃ — 130 4-biphenyl 3-CF₃—C₆H₄ — 131 4-(4′-propylbiphenyl) 3-CF₃—C₆H₄ — 132 4-(4′-t-butylbiphenyl) 3-CF₃—C₆H₄ — 133 4-(4′-C₂H₅O-biphenyl) 3-CF₃—C₆H₄ — 134 3-Cl—C₆H₄ 3-(3′-Cl-biphenyl) 191-193 135 3,4-di-Cl—C₆H₃ 3-(3′,4-di-Cl-biphenyl) 214-216 136 3,5-di-Cl—C₆H₃ 3-(3′,5′-di-Cl-biphenyl) 233-236 137 4-Cl—C₆H₄ 2-(4′-Cl-biphenyl) 230-232 138 4-(2-F-biphenyl) 4-Cl—C₆H₄ 255-258 139 4-biphenyl 4-Cl—C₆H₄ 280-282 140 3-Cl—C₆H₄ 2-(3′-Cl-biphenyl) 218-221 141 3,4-di-Cl—C₆H₃ 2-(3′,4′-di-Cl-biphenyl) 237-239 142 4-[3-F-(4-morpholin- 2-Cl-5-CF₃—C₆H₃ 232-234 4-yl)-C₆H₃] 143 benzo[b]thiophen-3-yl 4-biphenyl 270 144 thiophen-2-yl 4-biphenyl 213 (dec) 145 4-CN—C₆H₄ 2-CF₃—C₆H₄ 147-150 146 4-F—C₆H₄ 2-CF₃—C₆H₄ 147-150 147 3-biphenyl 3-CF₃—C₆H₄ 210-212 148 2,5-di-CH₃C₆H₃ 2-Cl-5-CF₃—C₆H₃ — 149 3-CH₃C₆H₄ 2-Cl-5-CF₃—C₆H₃ — 150 4-isopropyl-C₆H₄ 2-Cl-3-CF₃—C₆H₃ — 151 3-isopropyl-C₆H₄ 2-Cl-3-CF₃—C₆H₃ — 152 4-C₂H₅—C₆H₄ 2-Cl-3-CF₃—C₆H₃ — 153 4-CH₃—C₆H₄ 2-Cl-3-CF₃—C₆H₃ — 154 3,4-di-CH₃—C₆H₃ 2-Cl-3-CF₃—C₆H₃ — 155 3-CH₃—C₆H₄ 2-Cl-3-CF₃—C₆H₃ — 156 C₆H₅ 3-CF₃—C₆H₄ 224-226 157 3,5-di-Cl—C₆H₃ 3-{[(S)-1- 175-178 phenethyl]NHSO₂}—C₆H₄ 158 3,5-di-Cl—C₆H₃ 3-{[(R)-1- 195-198 phenethyl]urea}-C₆H₄ 159 3,5-di-Cl—C₆H₃ 3-{[(S)-1- 210-212 phenethyl]urea}-C₆H₄ 160 3,5-di-Cl—C₆H₃ 2-Cl-5-CF₃—C₆H₃ 244-247 161 3,5-di-Cl—C₆H₃ 4-benzyloxy-3-CH₃O—C₆H₃ 105-110 162 3,5-di-Cl—C₆H₃ 3-benzyloxy-4-CH₃O—C₆H₃ 214 (dec)

Example 163 Preparation of (5E)-(4-cyanobenzylidine)-3-(4-cyanophenyl)-4-hydroxyfuran-2(5H)-one

Step 1: A solution of 4-bromobenzonitrile (9.22 grams, 50.7 mmol), copper(I)iodide (0.63 grams, 3.3 mmol), triphenylphosphine (2.0 grams, 7.6 mmol) and palladium acetate (0.56 grams, 2.5 mmol) in 30 ml of THF is purged with nitrogen, treated with 20 ml of N-butylamine (202.4 mmol), stirred for 10 minutes, treated with 3.0 ml of propargyl alcohol (50.7 mmol), stirred at ambient temperatures for 3 h, treated with silica gel (20 grams) and concentrated under reduced pressure. The residue is purified by flash column chromatography (50% ether in hexane) to afford the desired product A in 91% yield (7.30 grams).

Reference: U.S. Pat. No. 6,239,280

Step 2: A mixture of the product A from above (7.00 grams, 44.6 mmol) and KOH (0.5 grams, 8.9 mmol) in acetonitrile is treated dropwise over 30 minutes with n-butylthiol 5.9 ml, 55.3 mmol), stirred for an additional 30 minutes, treated with silica gel (15 grams) and concentrated under reduced pressure. The residue is purified by flash column chromatography (50% ether in hexane) to give the desired product B in 71% yield (7.85 grams).

Reference: Tetrahedron Lett., 41, 141, 2000.

Step 3: A solution of the product B from above (7.50 grams, 30.4 mmol) in ethanol and 20 ml of 1N sulfuric acid is heated at 75° C. for 48 hours, cooled to ambient temperature and diluted with a mixture of ethyl acetate and brine. The organic phase is separated and dried over anhydrous sodium sulfate. Silica gel (10 grams) is added and the resultant mixture is concentrated under reduced pressure. The residue is purified by flash column chromatography (100% CH₂Cl₂) to give the desired product C in 72% yield (3.85 grams).

Reference: Tetrahedron Lett., 41, 141, 2000.

Step 4: A 2 M solution of lithium diisopropylamine (LDA) (27.5 ml, 55 mmol) is added to 100 ml of THF at −78° C. A solution of the product C from above (3.85 grams, 22 mmol) in 50 ml of THF is added to the LDA solution over 30 minutes at −78° C., stirred for another hour at −78° C., treated portionwise with carbonyl diimidazole (8.91 grams, 55 mmol) over 30 minutes, stirred for an additional 2 hours at −78° C., warmed to ambient temperature, stirred an additional hour, diluted with 60 ml of 3 M sulfuric acid and 100 ml of brine. The organic phase is separated and dried over anhydrous sodium sulfate. Silica gel (10 grams) is added and the mixture is concentrated under reduced pressure. Flash column chromatography (80% acetone in hexane) of the residue gives the desired product D in 37% yield (1.65 grams).

Reference: Tetrahedron Lett., 20, 4517, 1979.

Step 5: A solution of the product D from above (3.30 grams, 16.4 mmol) and potassium carbonate 2.04 grams, 14.8 mmol) in acetone is treated with dimethyl sulfate (3.5 ml), heated at reflux temperature for 1.5 hours, cooled to ambient temperature, treated with silica gel (5 grams) and concentrated under reduced pressure. Flash column chromatography (100% CH₂Cl₂) of the residue gives the desired product E in 64% yield (2.25 grams).

Reference: J. Chem. Soc. Perkin Trans. I, 1567, 1985.

Step 6: The product E from above (1.80 grams, 8.37 mmol) is dissolved in 1,2-dichloroethane heated to reflux temperature treated portionwise with N-bromo-succinimide (1.60 grams, 8.96 mmol) and AIBN (50 mg) over a 2 hour period, cooled and diluted with a mixture of CH₂Cl₂ and water. The organic phase is separated, dried over anhydrous sodium sulfate, treated with silica gel (5 grams) and concentrated under reduced pressure. Flash column chromatography (100% CH₂Cl₂) of the residue gives the desired product F in 67% yield (1.65 grams).

Reference: J. Chem. Soc. Perkin Trans. I, 1567, 1985.

Step 7: The product F from above (1.65 grams, 5.63 mmol) is dissolved in toluene and heated to 85° C., treated dropwise with a solution of triphenylphosphine (1.85 grams, 7.04 mmol) in toluene, stirred at 85° C. for 2 hours, cooled and filtered. The solid filtercake is dried under suction to give the desired product G in 85% yield (2.23 grams).

Reference: J. Chem. Soc. Perkin Trans. I, 1567, 1985.

Step 8: A solution of sodium (0.11 grams, 4.77 mmol) in ethanol is treated sequentially with 4′-cyano-4-phenyl benzaldehyde (1.03 grams, 4.96 mmol) and the product G from above (2.00 grams, 4.34 mmol), stirred at ambient temperature for 2 hours, and diluted with a mixture of water and toluene. The aqueous layer is separated, acidified to pH 1.0 with 4 N HCl and filtered. The solid filtercake is suction dried, washed twice with toluene and suction dried again to give the title product as a 7 to 1 mixture of Z to E isomers in 41% yield (0.68 grams). The two isomers may be separated by washing the E isomer out with chloroform.

Reference: J. Chem. Soc. Perkin Trans. I, 1567, 1985.

Examples 164-226 Preparation of 3-Aryl-4-hydroxyfuranone Derivatives

Using essentially the same procedures described in Example 163 hereinabove and employing a suitable arylcarboxaldehyde and appropriate Wittig reagent, and alkylating or acylating the 4-hydroxy group using conventional techniques, the compounds shown on Table III are obtained and identified by NMR and mass spectral analyses. Mass ions of the compounds are either M−H/M+H/M+Na or M+ depending upon method used. Example 174 is M-CO₂tBu. Unless otherwise noted, all compounds on Table III are the Z isomer.

Table III

Ex. Mass No. R R1 R2 Ion 164 H 4-CN—C₆H₄* 4-(4′-CN-biphenyl) 389 165 H 4-CN—C₆H₄** 4-Cl—C₆H₄ 323 166 H 4-CN—C₆H₄** 4-CN—C₆H₄ 314 167 H 4-CN—C₆H₄** 4-(4′-Cl-biphenyl) 398 168 H 4-Cl—C₆H₄ 4-(4′-CN-biphenyl) 399 169 H 4-Cl—C₆H₄* 4-(4′-CN-biphenyl) 399 170 H 4-Cl—C₆H₄** 4-CN—C₆H₄ 323 171 H 4-Cl—C₆H₄** 3-Cl—C₆H₄ 332 172 H 3-CF₃—C₆H₄ 4-Cl—C₆H₄ *** 173 CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 338 174 CO₂t-Bu 4-Cl—C₆H₄** 4-CN—C₆H₄ 322 175 CO₂C₆H₅ 4-Cl—C₆H₄** 4-CN—C₆H₄ 450 176 CO₂CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 388 177 CH₂CH═CH₂ 4-Cl—C₆H₄** 4-CN—C₆H₄ 364 178 H 4-CF₃—C₆H₄** 4-CN—C₆H₄ 356 179 H 4-CF₃—C₆H₄** 4-Cl—C₆H₄ 367 180 H 4-CF₃—C₆H₄** 4-CF₃—C₆H₄ 399 181 H 4-CF₃—C₆H₄** 4-(4′-Cl-biphenyl) 441 182 H 4-CF₃—C₆H₄** 4-(4′-CN-biphenyl) 432 183 H 4-CF₃—C₆H₄** 4-F—C₆H₄ 349 184 H 4-F—C₆H₄** 4-CN—C₆H₄ 306 185 H 4-F—C₆H₄** 4-Cl—C₆H₄ 315 186 H 4-F—C₆H₄** 4-CF₃—C₆H₄ 349 187 H 4-F—C₆H₄** 4-F—C₆H₄ 299 188 H 4-F—C₆H₄ 4-(4′-CN-biphenyl) 382 189 H 4-F—C₆H₄** 4-(4′-Cl-biphenyl) 391 190 H 3-Cl—C₆H₄** 4-CN—C₆H₄ 322 191 H 3-Cl—C₆H₄** 4-Cl—C₆H₄ 331 192 H 3-Cl—C₆H₄** 4-CF₃—C₆H₄ 365 193 H 3-Cl—C₆H₄** 4-(4′-Cl-biphenyl) 407 194 H 3-Cl—C₆H₄** 4-(4′-CN-biphenyl) 398 195 H 3-Cl—C₆H₄** 4-F—C₆H₄ 315 196 H 3-CF₃—C₆H₄** 4-CN—C₆H₄ 356 197 H 3-CF₃—C₆H₄** 4-F—C₆H₄ 349 198 H 3-CF₃—C₆H₄** 4-CF₃—C₆H₄ 399 199 H 3-CF₃—C₆H₄** 4(4′-Cl-biphenyl) 441 200 H 3-CF₃—C₆H₄** 4(4′-CN-biphenyl) 432 201 H 3-CN—C₆H₄** 4-CN—C₆H₄ 313 202 H 3-CN—C₆H₄** 4-Cl—C₆H₄ 322 203 H 3-CN—C₆H₄** 4-CF₃—C₆H₄ 356 204 H 3-CN—C₆H₄** 4-(4′-Cl-biphenyl) 398 205 H 3-CN—C₆H₄** 4-(4′-CN-biphenyl) 387 206 H 3-CN—C₆H₄** 4-F—C₆H₄ 306 207 H 4-CN—C₆H₄** 4-CF₃—C₆H₄ 356 208 H 4-CN—C₆H₄** 3-CF₃—C₆H₄ 356 209 H 4-CN—C₆H₄** 4-(4′-CF₃-biphenyl) *** 210 H 4-CN—C₆H₄** 4-F—C₆H₄ 306 211 H 4-Cl—C₆H₄** 4-CF₃—C₆H₄ 365 212 H 4-Cl—C₆H₄** 2-CF₃—C₆H₄ 365 213 H 4-Cl—C₆H₄** 4-(4′-CF₃-biphenyl) 441 214 H 4-Cl—C₆H₄** 4-F—C₆H₄ 315 215 H 4-(4′-Cl-biphenyl)** 4-CF₃—C₆H₄ 441 216 H 4-(4′-Cl-biphenyl)** 4-CN—C₆H₄ 398 217 H 4-(4′-Cl-biphenyl)** 4-Cl—C₆H₄ 409 218 H 4-(4′-CN-biphenyl)** 4-CF₃—C₆H₄ 389 219 H 4-(4′-CN-biphenyl)** 4-CN—C₆H₄ 432 220 H 4-(4′-CN-biphenyl)** 4-Cl—C₆H₄ 398 221 H 4-Cl—C₆H₄** 3,4-diCl—C₆H₃ *** 222 H 4-Cl—C₆H₄** 2,4-diCl—C₆H₃ *** 223 H 4-Cl—C₆H₄** 3-F-4-CF₃—C₆H₃ *** 224 H 4-CN—C₆H₄** 3,4-diCl—C₆H₃ *** 225 H 4-CN—C₆H₄** 2,4-diCl—C₆H₃ *** 226 H 4-CN—C₆H₄** 3-F-4-CF₃—C₆H₃ *** 227 H 4-F—C₆H₄** 4-OCF₃—C₆H₄ *** 228 H 4-CN—C₆H₄** 4-OCF₃—C₆H₄ *** 229 H 4-CN—C₆H₄** 4-OCHF₂—C₆H₄ *** 230 H 4-CN—C₆H₄** 4-OCF₂CHF₂—C₆H₄ *** 231 H 4-CN—C₆H₄** 5-chlorothiophen-2-yl *** 232 H 4-CN—C₆H₄** 2,2difluoro-1,3-dioxol- *** C₆H₃-5-yl 233 H 4-OCF₃—C₆H₄** 3,5-diCl—C₆H₃ 417 234 H 4-OCF₃—C₆H₄** 3,4-diF—C₆H₃ 384 235 H 4-OCF₃—C₆H₄** 4-n-propoxy-C₆H₄ 406 236 H 4-OCF₃—C₆H₄** 3,4-diCl—C₆H₃ 417 237 H 4-OCF₃—C₆H₄** 3-F-4-CF₃—C₆H₃ 434 238 H 4-OCF₃—C₆H₄** 5-chlorothiophen-2-yl 389 239 H 4-OCF₃—C₆H₄** thiophen-2-yl 354 240 H 4-OCF₃—C₆H₄** 4-phenoxy-C₆H₄ 440 241 H 4-OCF₃—C₆H₄** pyridine-3-yl 349 242 H 4-OCF₃—C₆H₄** 4-OCF₃—C₆H₄ 432 243 H 4-OCF₃—C₆H₄** 4-F—C₆H₄ 366 244 H 4-OCF₃—C₆H₄** 4-CN—C₆H₄ 373 245 H 4-OCF₃—C₆H₄** 4-Cl—C₆H₄ 383 246 H 4-OCF₃—C₆H₄** 4-OCHF₂—C₆H₄ 414 247 H 4-OCF₃—C₆H₄** 2-F-5-CF₃—C₆H₃ 434 248 H 4-OCF₃—C₆H₄** 4-CF₃—C₆H₄ 416 249 H 4-OCF₃—C₆H₄** 3-F-5-CF₃—C₆H₃ 434 250 H 4-OCF₃—C₆H₄** 2-F-4-CF₃—C₆H₃ 434 251 H 4-OCF₃—C₆H₄** 4-OCF₂CHF₂—C₆H₄ 464 252 H 4-OCF₃—C₆H₄** 2,2difluoro-1,3-dioxol- 428 C₆H₃-5-yl 253 H 4-OCF₃—C₆H₄** pyridine-4-yl 349 254 H 4-OCF₃—C₆H₄** pyridine-2-yl 349 255 H 4-OCF₃—C₆H₄** 3-Br-pyridine-2-yl 428 256 H 4-OCF₃—C₆H₄** 4-(4-F-phenyl)-pyridin-3-yl 442 257 H 4-OCF₃—C₆H₄** 4-(thiophen-2-yl)- 431 pyridin-3-yl 258 H 4-OCF₃—C₆H₄** 4-(4-OCF₃-phenyl)- 509 pyridin-3-yl 259 H 4-OCF₃—C₆H₄** 4-(5-Cl-thiophen-2-yl)- 465 pyridin-3-yl 260 H 4-OCF₃—C₆H₄** 4-(4-Cl-phenyl)-pyridin-3-yl 460 261 H 4-OCF₃—C₆H₄** 4-(3-Cl-phenyl)-pyridin-3-yl 460 262 H 4-OCF₃—C₆H₄** 4-Br-pyridine-3-yl 428 263 H 4-OCF₃—C₆H₄** 3-Cl-pyridine-4-yl 384 264 H 4-OCF₃—C₆H₄** 4-cyclopropylmethoxy-C₆H₄ 418 265 H 4-OCF₃—C₆H₄** 4-(5-Cl-thiophen-2-yl)-C₆H₄ 464 266 H 4-OCF₃—C₆H₄** 2-methyl-1H-imidazol-4-yl 352 267 H 4-OCF₃—C₆H₄** 5-chloro-1,3-dimethyl- 401 1H-pyrazol-4-yl 268 H 4-OCF₃—C₆H₄** 5-methyl-1-o-tolyl-1H- 442 pyrazol-4-yl 269 H 4-OCF₃—C₆H₄** 2-phenyl-1H-imidazol-4-yl 414 270 H 4-OCF₃—C₆H₄** 2-Cl-pyridine-3-yl 384 271 H 4-OCF₃—C₆H₄** 4-chloro-1-methyl-1H- 387 pyrazol-3-yl 272 H 4-OCF₃—C₆H₄** 5-(4-F-3-CF₃-phenyl)- 500 furan-2-yl 273 H 4-OCF₃—C₆H₄** 5-chloro-1-methyl-3- 455 trifluoromethyl-1H- imidazol-3-yl 274 H 4-OCF₃—C₆H₄** 5-bromo-1-methyl-1H- 431 imidazol-3-yl 275 H 4-OCF₃—C₆H₄** 1-(4-methoxyphenyl)-5- 458 methyl-1H-pyrazol-4-yl 276 H 4-OCF₃—C₆H₄** 1-(4-fluorophenyl)-5- 446 methyl-1H-pyrazol-4-yl 277 H 4-OCF₃—C₆H₄** 1-(phenyl)-5-methyl- 428 1H-pyrazol-4-yl 278 H 4-OCF₃—C₆H₄** 2-methanesulfanyl- 406 nicotinonitrile 279 H 4-OCF₃—C₆H₄** 5-bromo-furan-2-yl 417 280 H 4-OCF₃—C₆H₄** 6-phenoxy-pyridin-3-yl 441 281 H 4-OCF₃—C₆H₄** 4-(1,2,4-triazol-1-yl)-C₆H₄ 415 282 H 4-OCF₃—C₆H₄** 5-(pyridine-2-yl)- 431 thiphen-2-yl 283 H 4-OCF₃—C₆H₄** 5-(6-morpholino-4-yl)- 434 pyridin-3-yl 284 H 4-OCF₃—C₆H₄** 4-(4-methyl-piperazin- 446 1-yl)-C₆H₄ 285 H 4-OCF₃—C₆H₄** 4-(thiophen-2-yl)-C₆H₄ 430 286 H 4-OCF₃—C₆H₄** 4-(pyrrol-1-yl)-C₆H₄ 413 287 H 4-OCF₃—C₆H₄** 4-(4′-Cl-biphenyl) 459 288 H 4-OCF₃—C₆H₄** 4-(4′-CN-biphenyl) 449 289 H 4-OCF₃—C₆H₄** 2,5-dimethyl-2H- 366 pyrazol-3-yl 290 H thiophen-2-yl 4-CN—C₆H₄ 295 291 H thiophen-2-yl 4-Cl—C₆H₄ 305 292 H thiophen-2-yl 4-CF₃—C₆H₄ 338 293 H 5-chlorothiophen-2-yl 4-Cl—C₆H₄ 339 294 H 5-chlorothiophen-2-yl 4-CN—C₆H₄ 330 295 H 5-chlorothiophen-2-yl 4-CF₃—C₆H₄ 373 296 H 5-chlorothiophen-2-yl 4-OCF₃—C₆H₄ 389 297 H 5-chlorothiophen-2-yl 4-OCHF₂—C₆H₄ 371 298 H 5-chlorothiophen-2-yl 3,4-diCl—C₆H₃ 374 299 H 5-chlorothiophen-2-yl 3,4-diF—C₆H₃ 341 300 H 5-chlorothiophen-2-yl 4-F-3-CF₃—C₆H₃ 391 301 H 5-chlorothiophen-2-yl 4-F—C₆H₄ 323 302 H 5-chlorothiophen-2-yl 3-F-4-CF₃—C₆H₃ 391 303 H 5-chlorothiophen-2-yl 4-(4′-Cl-biphenyl) 415 304 H 5-chlorothiophen-2-yl 4-cyclopropylmethoxy-C₆H₄ 375 305 H 5-chlorothiophen-2-yl 4-OCF₂CHF₂—C₆H₄ 421 306 H 5-chlorothiophen-2-yl 5-chlorothiophen-2-yl 345 307 H 5-chlorothiophen-2-yl 4-Br-pyridine-3-yl 385 308 H 5-chlorothiophen-2-yl 2,2difluoro-1,3-dioxol- 385 C₆H₃-5-yl 309 H 5-chlorothiophen-2-yl 4-(4-Cl-phenyl)-pyridin-3-yl 416 310 H 5-chlorothiophen-2-yl 4-(4-F-phenyl)-pyridin-3-yl 400 311 H 5-chlorothiophen-2-yl 4-(4-OCF₃-phenyl)- 466 pyridin-3-yl 312 H 5-chlorothiophen-2-yl 4-(5-Cl-thiophen-2-yl)- 422 pyridin-3-yl 313 H 5-chlorothiophen-2-yl 4-(5-Cl-thiophen-2-yl)-C₆H₄ 421 314 H 4-Cl—C₆H₄** 4-cyclopropylmethoxy-C₆H₄ *** 315 H 4-Cl—C₆H₄** 4-SCF₃—C₆H₄ *** 316 H 4-Cl—C₆H₄** 2-methanesulfanyl- *** nicotinonitrile 317 H 4-Cl—C₆H₄** 5-(4-F-3-CF₃-phenyl)- *** furan-2-yl 318 H 4-Cl—C₆H₄** 6-phenoxy-pyridin-3-yl *** 319 H 4-Cl—C₆H₄** 1-(4-fluorophenyl)-5- *** methyl-1H-pyrazol-4-yl 320 H 4-CN—C₆H₄** 6-phenoxy-pyridin-3-yl *** 321 H 4-CN—C₆H₄** 1-(4-fluorophenyl)-5- *** methyl-1H-pyrazol-4-yl 322 H 4-CN—C₆H₄** 2-methanesulfanyl- *** nicotinonitrile *E isomer **Mixture of Z and E isomers ***NMR analysis only

Example 323 Evaluation of the Inhibitory Activity of Test Compounds Against Enzymes Which Catalyze Bacterial Cell Wall Biosynthesis

S. aureus and E. coli UDP-N-acetylalucosamine enolpyruvoyl Transferase, MurA

Preparation of Enzyme Solution:

The enzyme solution is prepared by admixing the following:

50 mM Tris/HCl pH 8.0, 500 ml 1 M Tris, 5 mM DTT, 50 ml 1 M DTT, 20% Glycerol 4 ml 50% Glycerol, add water to 10 ml.

Preparation of Stop Solution:

The stop solution is prepared by mixing the following:

4.2% ammonium molybdate in 4N HCl, 8.4 g/200 ml 4N HCl, 0.045% malachite green, 90 mg/200 ml water, then stir 1 part ammonium molybdate with 2 parts malachite green for 30 min.

A procedure similar to that described by C. T. Walsh in Biochemistry 33, 10646-10651, is used to evaluate the inhibitory activity of test compounds against MurA, the enzyme which catalyzes the first step of bacterial cell wall biosynthesis. Experiments are performed by adding a solution of test compound (in a mixture of dimethylsulfoxide and water) and an enzyme solution to a well. After a pre-incubation period of 10 minutes at 37° C., Tris/BME buffer and assay buffer are added. A start point optical density (OD₀) reading is taken at 340 nm immediately following the addition of assay buffer. After incubation for 1 hr at 37° C., the stop solution is added and the color is allowed to develop for 30 minutes. An end point OD₁ reading at 660 nM is then taken. The % inhibition at a concentration of 25 μg/ml is calculated for each test compound using the formula:

${\%\mspace{14mu}{inhibition}} = {100 - {\frac{{OD}_{1} - {{OD}_{0}\mspace{14mu}{for}\mspace{14mu}{test}\mspace{14mu}{compound}}}{{OD}_{1} - {{OD}_{0}\mspace{14mu}{mean}\mspace{14mu}{of}\mspace{14mu}{control}}} \times 100}}$

Using these values, the concentration required to give 50% inhibition (IC₅₀) for each test compound is determined by linear regression analysis. The results are shown in Table III.

S. aureus and E. coli Enopyruvyl-UPD-N-acetylglucosamine reductase, Mur B

Preparation of Tris/BME Buffer:

Dilute 17.5 uL of aqueous 5 mM BME (2-mercaptoethanol) to 50 mL with 50 mM Tris/HCl (pH 8.0).

Preparation of Enzyme Solution:

Dilute aqueous MurB stock solution (0.94 mg/mL) with 200 parts 50 mM Tris/2-BME buffer. The final MurB concentration is 4.7 μg/mL.

Synthesis of Substrate for MurB (MurA product EP-UDP-GluNAc):

A mixture of 13 mg UDP-N-acetylglucosamine and 5.5 mg phosphoenolpyruvate are dissolved in 10 mL Tris/BME buffer forming 2 mM concentrations of each reagent in solution. The solution is incubated with 300 μg purified MurA at 37° C. overnight to give approximately 70-80% product yield.

Preparation of Assay Buffer:

The assay buffer is prepared in water from reagents with the following final concentrations: 100 mM Tris/HCl (pH 8.0), 200 μM NADPH, 100 μM MurB substrate, 10 μM 2-mercaptoethanol, and 10 μM KCl.

A procedure similar to that described by Dhalla et al., in Biochemistry 1995, 34, 5390, is used to evaluate the inhibitory activity of test compounds against MurB, the enzyme which catalyzes the second step of bacterial cell wall biosynthesis. Experiments are performed by adding 20 μL of a solution of test compound in a mixture of dimethylsulfoxide and water and 30 μL of enzyme solution to a well. After a pre-incubation period of 20 mins. at 23° C., 50 μL of Tris/BME buffer and 100 μL of assay buffer are added. A start point optical density (OD₀) reading is taken at 340 μM immediately following the addition of assay buffer using a Molecular Devices Spectra Max 250 with SoftMax software. After a 20 min. incubation period at 23° C., an endpoint OD₁ reading is taken at 340 μM. Controls are performed using the same procedure and employing 20 μL of a blank dimethylsulfonide and solvent mixture in place of the test compound solution. The % inhibition at concentrations of 10 μg/ml and 25 μg/ml are calculated using the formula:

${\%\mspace{14mu}{inhibition}} = {100 - {\frac{{{Sample}\mspace{14mu}{OD}_{1}} - {{Sample}\mspace{14mu}{OD}_{0}}}{{{Control}\mspace{14mu}{OD}_{1}} - {{Control}\mspace{14mu}{OD}_{0}}} \times 100}}$

Using these values, the IC₅₀ for each test compound is determined by linear regression analysis. The results are shown in Table III.

S. aureus and E. coli Uridine-diphosphate-N-acetylmuramoyl: L-alanine lipase, MurC

Preparation of Buffer:

The buffer is prepared from aqueous reagents with the following final concentrations: 83 mM Tris/HCl (pH 8.0), 50 mM MgC₁₂, and 2 mM ATP.

Preparation of Enzyme Solution:

A 1 mg/mL stock solution of MurC is prepared in a buffer consisting of 20 mM Tris/HCl (pH 8.5) with 2.5 μM BME. The stock solution is further diluted with the buffer to give a final enzyme concentration of 100 μg/mL for the E. coli stock solution and 70 μg/mL for the S. aureus stock solution.

Preparation of Test Compound Solutions:

All test solutions are prepared in DMSO as 10 mg/mL, then diluted with 50 mM Tris/HCl (pH 8.5) to 100 μg/m L.

Preparation of Stop Solution:

The stop solution is prepared by stirring 1 part 4.2% ammonium molybdate in 4N HCl with 2 parts 0.045% malachite green for 30 min.

In this evaluation, the inhibitory activity of a test compound against MurC, the enzyme which catalyzes the third step of bacterial cell wall biosynthesis is determined. Experiments are performed by adding 2.5 μl buffer, 2.5 μl 0.5M NH₄SO₂, 5 μl 2 μM L-Ala, 5 μl enzyme solution and 6.5 μl test compound solution to each well in a 96-well microplate. After a pre-incubation period of 10 mins. at 23° C., 3.75 μl of a 0.75 μM solution of UDP-MurNac is added to each well. Following an incubation period of 10 mins. at 37° C., 210 μl stop solution and 50 μl of a 34% w/v sodium citrate solution are added and color is allowed to develop for 10 mins. at 23° C. (Lanzetta et al., Analytical Biochemistry, 1979, 95) Optical density readings are taken at 660 nm using a Molecular Devices Spectra Max 250 with Soft Max software. Controls are performed using the same procedure and omitting the addition of UDP-MurNac. The % inhibition of a concentration of 25 μg/ml is calculated for each test compound using the formula:

${\%\mspace{14mu}{inhibition}} = {100 - {\frac{{Sample}\mspace{14mu}{OD}}{{mean}\mspace{14mu}{Control}\mspace{14mu}{OD}} \times 100}}$

Using these values the IC₅₀ is determined by linear regression analysis. The results are shown in Table III.

S. aureus and E. coli Uridine-diphosphate-N-acetylmuramoyl-L-alanine: D-glutamate ligase, MurD

Preparation of Buffer:

The buffer is prepared from aqueous reagents with the following final concentrations: 83 mM Tris/HCl (pH 8.0), 50 mM MgCl₂, and 2 mM ATP.

Preparation of Enzyme Solution:

A 1 mg/mL stock solution of MurD is prepared in a buffer consisting of 20 mM Tris/HCl (pH 8.5) with 2.5 μM BME. The stock solution is further diluted with the buffer to give a final enzyme concentration of 22 μg/mL for the E. coli stock solution and 11.1 μg/mL for the S. aureus stock solution.

Preparation of Test Compound Solutions:

All test solutions are prepared in DMSO as 10 mg/mL, then diluted with 50 mM Tris/HCl (pH 8.5) to 100 μg/mL.

Preparation of Stop Solution:

The stop solution is prepared by stirring 1 part 4.2% ammonium molybdate in 4N HCl with 2 parts 0.045% malachite green for 30 min.

In this evaluation, the inhibitory activity of a test compound against MurD, the enzyme which catalyzes the fourth step of bacterial cell wall biosynthesis is determined. Using essentially the same procedure described hereinabove for evaluating MurC and employing MurD as the enzyme, the % inhibition at 25 μg/ml and the IC₅₀ for each test compound is determined. The results are shown in Table IV, wherein (E) designates E. coli and (S) designates S. aureus.

TABLE IV Ex. MurA MurB MurC MurD No. IC₅₀ (μg/mL) IC₅₀ (μg/mL) IC₅₀ (μg/mL) IC₅₀ (μg/mL) 4 >25 (E) 10 (E); 10 (S) 7 (E); 16 (S) >25 (E); 24 (S) 5 >25 (E) 8 (E); 6 (S) 6 (E) >25 (E) 6 >25 (E) >25 (E); 21 (S) 16 (E) >25 (E) 7 >25 (E) 21 (E) 13 (E) >25 (E) 8 >25 (E) 11 (E) 6 (E) >25 (E) 9 >25 (E) 16 (E) >25 (E) >25 (E) 10 1 (E) 6 (E) 4 (E); 7 (S) 21 (E); 13 (S) 11 1 (E) 6 (E) 4 (E); 5 (S) 21 (E); 11 (S 12 >25 (E) >25 (E) 15 (E) >25 (E) 13 0.5 (E) 12 (E) 4 (E); 15 (S) >25 (E); 20 (S) 14 5 (E) >25 (E) 13 (E); 22 (S) >25 (E); >25 (S) 15 >25 (E) >25 (E) 17 (E); >25 (S) >25 (E); >25 (S) 16 >25 (E) >25 (E) 7 (E); 22 (S) >25 (E); >25 (S) 17 >25 (E) >24 (E) 10 (E); >25 (S) >25 (E); >25 (S) 18 6 (S) 6 (E); 5 (S) 10 (S) 18 (S) 19 17 (S) 20 (E); 10 (S) 6 (E); 19 (S) >25 (E); 17 (S) 20 >25 (S) 3 (E); 3 (S) 11 (E); 15 (S) >25 (E); 19 (S) 21 5 (S) 5 (E); 3 (S) 20 (S) 8 (S) 22 9 (S) 6 (E); 6 (S) 12 (S) 17 (S) 23 14 (S) 4 (E); 5 (S) 12 (S) 10 (S) 24 7 (S) 4 (E); 2 (S) 12 (S) 11 (S) 25 5 (S) 2 (E); 2 (S) 12 (S) 14 (S) 26 4 (S) 3 (E); 2 (S) 6 (S) 9 (S) 27 2 (S) 3 (E); 2 (S) >25 (S) 24 (S) 28 10 (S) 3 (E); 3 (S) >25 (S) >25 (S) 29 2 (S) 2 (E); 2 (S) 24 (S) 17 (S) 30 3 (S) 2 (E); 2 (S) >25 (S) >25 (S) 31 2 (S) 2 (E); 2 (S) >25 (S) 10 (S) 32 10 (S) 6 (E); 3 (S) 12 (S) 9 (S) 33 4 (S) 2 (E); 2 (S) >25 (S) >25 (S) 34 22 (S) 6 (S) 21 (S) >25 (S) 35 >25 (S) 6 (S) 8 (S) 17 (S) 36 6 (S) 3 (S) 5 (S) 9 (S) 37 >25 (S) 10 (S) 10 (S) 19 (S) 38 >25 (S) 8 (S) 7 (S) 6 (S) 39 15 (S) 8 (E); 4 (S) 8 (S) 15 (S) 40 14 (S) — 4 (S) 7 (S) 41 >25 (E) >25 (E) 13 (E) >25 (E) 42 20 (E) 10 (E) 6 (E); 18 (S) >25 (E); >25 (S) 43 20 (E) 6 (E); 5 (S) 4 (E); 21 (S) >25 (E); >25 (S) 44 18 (E) 7 (E) 6 (E) >25 (E) 45 >25 (E) 2 (E) 10 (E) >25 (E); >25 (S) 46 >25 (E) >25 (E) 16 (E) >25 (E) 47 >25 (E) 23 (E); 10 (S) 11 (E) >25 (E); >25 (S) 48 >25 (E) >25 (E) 13 (E) >25 (E) 49 17 (E) 11 (E) 9 (E) >25 (E) 50 16 (E) >25 (E) 9 (E) >25 (E) 51 >25 (E) >25 (E) 9 (E); 20 (S) >25 (E); >25 (S) 52 >25 (E) >25 (E) 17 (E); >25 (S) 23 (E); 20 (S) 53 >25 (E) 6 (E) 5 (E); 7 (S) 5 (E); 16 (S) 54 >25 (E) 8 (E) 5 (E); 11 (S) >25 (E); >25 (S) 55 >25 (E) 4 (E) 11 (E); 22 (S) 24 (E); 15 (S) 56 >25 (E) >25 (E) 5 (E); 11 (S) >25 (E); 19 (S) 57 >25 (E) 6 (E) 20 (E) 17 (E); 19 (S) 58 >25 (E) >25 (E) 14 (E) >25 (E); >25 (S) 59 17 (E) 6 (E) 6 (E) 5 (E); 5 (S) 60 >25 (E) >25 (E) 14 (E) >25 (E); 22 (S) 61 >25 (E) >25 (E) 14 (E) >25 (E); 19 (S) 62 7 (E) 15 (E) 5 (E) 5 (E); >25 (S) 63 1 (E) 3 (E) 17 (E); 23 (S) 6 (E); >25 (S) 64 6 (E) 3 (E) 12 (E) 6 (E); 8 (S) 65 >25 (E) 10 (E) 3 (E) 24 (E); 15 (S) 66 3 (E) 2 (E) 3 (E) 21 (E); 5 (S) 67 3 (E) 1 (E) 6 (E); 18 (S) 9 (E); 8 (S) 68 3 (E) 3 (E) 9 (E) 11 (E); 11 (S) 69 8 (E) 5 (E) 5 (S) 19 (E); 7 (S) 70 15 (S) 7 (E); 5 (S) 5 (E); 8 (S) 17 (E); 9 (S) 71 >25 (S) 10 (E); 10 (S) 11 (E); 20 (S) >25 (E); 24 (S) 72 >25 (S) 21 (E); 20 (S) >25 (E); >25(S) >25 (E); >25 (S) 73 >25 (S) >25 (E); 12 (S) 19 (E); 23 (S) >25 (E); >25 (S) 74 >25 (S) 22 (E); 10 (S) 19 (E); 18 (S) >25 (E); >25 (S) 75 >25 (S) >25 (E); 24 (S) 18 (E); 20 (S) >25 (E); >25 (S) 76 6 (S) 7 (E); 5 (S) 5 (E); 18 (S) 23 (E); >25 (S) 77 >25 (S) 21 (E); 10 (S) 9 (E); 15 (S) >25 (S) 78 >25 (S) 3 (E0; 13 (S) 21 (S) >25 (S) 79 14 (S) 6 (E); 1 (S) 24 (S) 14 (S) 80 15 (S) 3 (E); 1 (S) 18 (S) 13 (S) 81 >25 (S) 23 (E); 15 (S) 16 (S) >25 (S) 99 4 (E) 6 (E) 4 (E) >25 (E) 100 >25 (E) 24 (E) 13 (E); 16 (S) >25 (E); 24 (S) 101 23 (E) >25 (E) 18 (E); 23 (S) >25 (E); >25 (S) 102 23 (E) 5 (E); 10 (S) 6 (E); 19 (S) >25 (E); 15 (S) 103 >25 (E) 6 (E) 16 (E) >25 (E) 104 >25 (E) 24 (E) 5 (E); 19 (S) >25 (E); >25 (S) 105 19 (E) 6 (E) 5 (E); 12 (S) 12 (E); >25 (S) 106 9 (E) 12 (E) 9 (E); 12 (S) >25 (E); 16 (S) 107 14 (E) 4 (E) 6 (E) >25 (E); 17 (S) 108 19 (E) 10 (E) 6 (E) >25 (E); 15 (S) 109 5 (E) 4 (E) 10 (E) >25 (E) 110 7 (E) 5 (E) 9 (E) 19 (E) 111 >25 (E) 11 (E) >25 (E) >25 (E) 112 15 (E) 5 (E) 10 (E) >25 (E) 113 4 (E) 3 (E) >25 (E) >25 (E) 114 1 (E) 1 (E) 10 (E) 16 (E) 115 5 (E) 5 (E) >25 (E) >25 (E) 116 3 (E) 4 (E) >25 (E) >25 (E) 117 10 (E) 7 (E) >25 (E) >25 (E) 118 15 (E) 18 (E) 19 (E) >25 (E) 119 1 (E) 1 (E) 2 (E) 6 (E) 120 4 (E) 5 (E) 23 (E) 16 (E) 121 9 (E) 7 (E) 9 (E) 25 (E) 122 16 (E) 14 (E) >25 (E) >25 (E) 123 21 (E) 3 (E) >25 (E) >25 (E) 124 14 (E) 12 (E) >25 (E) >25 (E) 125 4 (E) 5 (E) 1 (E) 20 (E) 126 3 (E) 1 (E) 5 (E) 9 (E) 127 4 (E) 6 (E) >25 (E) >25 (E) 128 4 (E) 5 (E) 24 (E) >25 (E) 129 2 (E) 2 (E) 7 (E) 7 (E) 130 17 (E) 9 (E) 8 (E) >25 (E) 131 4 (E) 2 (E) 18 (E) 9 (E) 132 3 (E) 3 (E) 24 (E) 8 (E) 133 20 (E) 12 (E) 22 (E) 22 (E) 134 5 (E) 4 (E); 2 (S) 5 (E); 21 (S) 6 (E); 8 (S) 135 2 (E) 3 (E); 3 (S) 6 (E) 6 (S) 136 1 (S) 3 (E); 2 (S) 11 (E); >25 (S) 6 (E); 10 (S) 137 13 (S) 21 (E); 3 (S) 17 (E); 23 (S) 18 (S) 138 7 (S) 22 (E); 3 (S) 5 (E); 8 (S) 14 (S) 139 >25 (E) 6 (E) 16 (E) >25 (E) 140 11 (S) 4 (E); 3 (S) 8 (S) 20 (S) 141 3 (S) 2 (E); 2 (S) >25 (S) 3 (S) 142 >25 (S) 10 (E); 21 (S) >25 (S) >25 (S) 143 >25 (S) 7 (E); 4 (S) 5 (S) 10 (S) 144 >25 (S) 20 (E); 10 (S) 10 (S) 20 (S)

Example 324 Evaluation of the Minimum Inhibitory Concentration of Test Compounds Against A Variety of Bacterial Strains

In this evaluation the minimal inhibitory concentration (MIC) of test compounds against Gram positive and Gram negative bacteria is performed using the microdilution broth method as recommended by the National Committee for Clinical Laboratory Standards (Approved Standards M7-A5 2000). Mueller-Hinton broth is used for the enterobacteriaceae, staphylococci and enterococci. Streptococci are also tested in Mueller-Hinton broth supplemented with 5% horse blood (LHB). Test organisms include recent clinical isolates that are resistant to methicillin, penicillin and/or vancomycin. Microtiter plates containing 50 μl per well of two-fold serial dilutions of the test compounds in the appropriate broth are inoculated with 50 μl of inoculum to a final concentration of 1−5×10⁵ CFU/ml. The MIC is determined after incubation for 18-22 hours at 35° C. in ambient air. The results are shown in Table V.

TABLE V MIC (μg/mL) Ex. S. aureus S. aureus E. faecalis E. faecalis S. pneumo No. GC 1131 GC 4543 GC 4555 GC 2242 GC 1894 4 16 16 32 8 1 5 8 8 16 8 0.5 6 32 64 >128 32 8 7 32 64 64 32 2 8 8 8 16 4 0.25 9 32 >128 64 8 <0.125 10 4 2 8 1 <0.125 11 4 2 8 1 <0.125 12 64 64 >128 64 2 13 64 >128 >128 >128 2 14 >128 >128 4 64 64 15 64 64 64 32 0.5 16 64 >128 64 64 0.5 17 32 >128 64 32 <0.125 18 4 4 16 8 0.5 19 2 2 8 8 0.5 20 4 4 16 16 0.5 21 1 0.5 4 2 0.5 22 4 4 16 8 1 23 8 4 8 8 1 24 2 1 4 4 0.5 25 1 0.5 4 2 0.25 26 2 1 4 2 <0.125 27 0.5 0.5 2 1 0.5 28 1 0.5 4 2 <0.125 29 0.5 0.5 2 0.5 <0.125 30 2 1 4 4 0.25 31 0.5 0.25 2 1 0.25 32 2 2 8 4 0.5 33 0.5 0.5 2 1 0.5 34 32 32 64 64 4 35 8 8 16 8 2 36 4 4 8 4 1 37 16 16 32 16 8 38 8 8 32 16 1 39 2 4 8 4 1 40 1 1 2 2 <0.125 41 32 64 64 32 32 42 8 8 32 8 8 43 8 8 16 4 1 44 4 8 16 8 1 45 16 4 8 4 2 46 64 32 32 64 16 47 16 32 64 32 16 48 32 64 >128 32 8 49 8 8 32 8 0.5 50 8 4 32 8 4 51 >128 16 32 8 <0.125 52 16 16 8 4 0.5 53 16 16 8 4 0.5 54 8 16 32 4 <0.125 55 4 1 4 1 <0.125 56 16 32 32 8 4 57 32 4 8 2 <0.125 58 8 16 >128 16 <0.125 59 >128 >128 8 8 32 60 16 16 32 8 8 61 16 16 32 16 8 62 >128 >128 64 32 64 63 4 0.5 1 0.5 <0.125 64 16 8 8 2 <0.125 65 8 8 16 4 <0.125 66 2 1 2 0.5 <0.125 67 1 0.5 2 0.5 <0.125 68 2 2 2 1 <0.125 69 2 1 0.5 0.5 0.25 70 2 1 2 2 0.5 71 8 8 8 4 0.5 72 >128 >128 >128 >128 32 73 >128 >128 >128 >128 64 74 64 >128 >128 >128 32 75 64 >128 64 >128 32 76 >128 >128 >128 >128 64 77 >128 64 >128 >128 64 78 32 32 64 64 2 79 2 1 8 4 0.5 80 2 1 8 4 1 81 8 8 32 16 1 99 4 2 16 4 0.25 100 >128 >128 >128 >128 64 101 >128 >128 >128 64 64 102 8 4 16 4 1 103 >128 64 64 32 0.5 104 16 32 64 32 0.5 105 8 8 8 2 <0.125 106 2 2 1 0.25 0.25 107 4 2 8 2 0.25 108 2 2 8 2 1 109 2 2 4 1 0.25 110 2 2 4 1 0.25 111 32 16 16 1 0.25 112 2 4 8 2 0.25 113 1 2 4 1 0.25 114 1 1 2 0.5 0.25 115 4 4 2 0.25 0.25 116 8 8 4 4 <0.125 117 64 32 32 8 0.5 118 16 16 32 16 4 119 2 2 2 2 0.5 120 16 16 8 4 0.5 121 4 2 16 8 0.5 122 16 16 32 8 1 123 16 16 8 4 0.5 124 32 32 32 16 1 125 2 2 8 4 0.5 126 1 1 4 1 0.25 127 4 2 4 2 0.25 128 8 4 8 2 0.25 129 2 2 4 2 0.25 130 4 4 4 8 0.5 131 32 16 8 4 0.25 132 16 16 8 4 0.25 133 32 32 16 8 0.5 134 >128 1 8 4 1 135 32 1 4 4 1 136 0.25 0.25 1 0.5 0.25 137 8 8 4 4 2 138 4 4 8 4 0.5 139 16 16 8 4 1 140 1 1 4 4 1 141 0.5 0.25 1 0.5 <0.125 142 64 >128 >128 >128 8 143 8 8 32 4 1 144 16 16 >128 32 2

Example 325 Comparative Evaluation of the Efficacy of a 3-Aryl-4-hydroxyfuranone Compound Against Blowfly Larvae

In this evaluation, filter paper discs are treated with an acetone solution of test compound and allowed to dry. Bovine serum and newly emerged larvae of blowfly, Lucilia sericata, are added to the treated filter paper. Mortality is assessed at 24 h and 48 h. When more than one evaluation is performed, the data are averaged. The results, at a dose rate of 20 ppm, are shown in Table VI, wherein all test compounds are the Z isomers unless otherwise noted.

TABLE VI

% Mortality R R1 R2 24 h 48 h H 4-biphenyl 1-naphthyl 100 100 H 3,5-diCl—C₆H₃ 4-(3-OMe-3′CF₃-biphenyl) 0 0 CH₃ 3-CF₃—C₆H₄ C₆H₅ 0 0 H 4-CN—C₆H₄* 4-(4′-CN-biphenyl) 0 0 H 4-CN—C₆H₄** 4-Cl—C₆H₄ 25 100 H 4-CN—C₆H₄** 4-CN—C₆H₄ 40 100 H 4-CN—C₆H₄** 4-(4′-Cl-biphenyl) 0 100 H 4-Cl—C₆H₄ 4-(4′-CN-biphenyl) 0 0 H 4-Cl—C₆H₄* 4-(4′-CN-biphenyl) 0 100 H 4-Cl—C₅H₄** 4-CN—C₆H₄ 0 90 H 4-Cl—C₆H₄** 3-Cl—C₆H₄ 0 0 CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 0 0 CO₂t-Bu 4-Cl—C₆H₄** 4-CN—C₆H₄ 0 0 CO₂C₆H₅ 4-Cl—C₆H₄** 4-CN—C₆H₄ 0 0 CO₂CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 0 0 CH₂CH═CH₂ 4-Cl—C₆H₄** 4-CN—C₆H₄ 0 0 H 4-CF₃—C₆H₄** 4-CN—C₆H₄ 100 100 H 4-CF₃—C₆H₄** 4-Cl—C₆H₄ 100 100 H 4-CF₃—C₆H₄** 4-CF₃—C₆H₄ 100 100 H 4-CF₃—C₆H₄** 4-(4′-Cl-biphenyl) 0 65 H 4-CF₃—C₆H₄** 4-(4′-CN-biphenyl) 0 0 H 4-CF₃—C₆H₄** 4-F—C₆H₄ 100 100 H 4-F—C₆H₄** 4-CN—C₆H₄ 0 0 H 4-F—C₆H₄** 4-Cl—C₆H₄ 0 0 H 4-F—C₆H₄** 4-CF₃—C₆H₄ 0 0 H 4-F—C₆H₄** 4-F—C₆H₄ 0 0 H 4-F—C₆H₄ 4-(4′-CN-biphenyl) 0 0 H 4-F—C₆H₄** 4-(4′-Cl-biphenyl) 0 0 H 3-Cl—C₆H₄** 4-CN—C₆H₄ 0 0 H 3-Cl—C₆H₄** 4-Cl—C₆H₄ 0 0 H 3-Cl—C₆H₄** 4-CF₃—C₆H₄ 60 75 H 3-Cl—C₆H₄** 4-(4′-Cl-biphenyl) 0 0 H 3-Cl—C₆H₄** 4-(4′-CN-biphenyl) 0 0 H 3-Cl—C₆H₄** 4-F—C₆H₄ 0 0 H 3-CF₃—C₆H₄** 4-CN—C₆H₄ 20 20 H 3-CF₃—C₆H₄** 4-F—C₆H₄ 100 100 H 3-CF₃—C₆H₄** 4-CF₃—C₆H₄ 100 100 H 3-CF₃—C₆H₄** 4-(4′-Cl-biphenyl) 0 0 H 3-CF₃—C₆H₄** 4-(4′-CN-biphenyl) 0 0 H 3-CN—C₆H₄** 4-CN—C₆H₄ 0 0 H 3-CN—C₆H₄** 4-Cl—C₆H₄ 0 0 H 3-CN—C₆H₄** 4-CF₃—C₆H₄ 0 0 H 3-CN—C₆H₄** 4-(4′-Cl-biphenyl) 0 0 H 3-CN—C₆H₄** 4-(4′-CN-biphenyl) 20 20 H 3-CN—C₆H₄** 4-F—C₆H₄ 0 0 H 4-CN—C₆H₄** 4-CF₃—C₆H₄ 100 100 H 4-CN—C₆H₄** 3-CF₃—C₆H₄ 0 90 H 4-CN—C₆H₄** 4-(4′-CF₃-biphenyl) 0 25 H 4-CN—C₆H₄** 4-F—C₆H₄ 0 0 H 4-Cl—C₆H₄** 4-CF₃—C₆H₄ 100 100 H 4-Cl—C₆H₄** 2-CF₃—C₆H₄ 10 10 H 4-Cl—C₆H₄** 4-(4′-CF₃-biphenyl) 0 0 H 4-Cl—C₆H₄** 4-F—C₆H₄ 0 0 H 4-(4′-Cl-biphenyl)** 4-CF₃—C₆H₄ 0 0 H 4-(4′-Cl-biphenyl)** 4-CN—C₆H₄ 0 0 H 4-(4′-Cl-biphenyl)** 4-Cl—C₆H₄ 0 0 H C₆H₅ 3-CF₃—C₆H₄ 0 0 H 4-Cl—C₆H₄ 4-OMe—C₆H₄ 0 0 H 3-CH₂OH—C₆H₄ 1-naphthyl 0 0 H 3,5-diCl—C₆H₃ 3-F-4-[1-(4-CO₂C₂H₅- 0 0 piperazinyl)]-C₆H₃ H 3,5-diCl—C₆H₃ 3-Cl-4-{1-[4-(2-Cl—C₆H₄)- 0 0 piperazinyl]}-C₆H₃ H 4-CN—C₆H₄ 4-(4′-CN-biphenyl) 0 0 H 3-CH₂OH—C₆H₄ 4-(3′-CH₂OH-biphenyl) 0 0 H 3,5-diCl—C₆H₃ 4-(3′,5′-diCl-biphenyl) 0 0 H 4-Cl—C₆H₄ 4-(4′-Cl-biphenyl) 0 0 H 4-(4′-t-Bu- 4-biphenyl 0 0 biphenyl) H 4-(biphenyl) 4-CF₃—C₆H₄ 0 0 H 3-CF₃—C₆H₄ 4-(3′-CF₃-biphenyl) 0 0 H 3-CF₃—C₆H₄ 4-(3-F-biphenyl) 0 0 H 2-CH₂OH—C₆H₄ 4-(2′-CH₂OH-biphenyl) 0 0 H 3-N(COCH₃)C₆H₄ 4-[3′-N(COCH₃)-biphenyl] 0 0 *E isomer **Mixture of Z and E isomers

Example 326 Evaluation of the Efficacy of a 3-Aryl-4-Hydroxyfuranone Against Nematodes

In this evaluation, cultures of C. elegans are maintained on E. coli lawns on Nematode Growth Agar at 20° C. New cultures are established twice a week. Nematodes for testing are rinsed from plates using M9 Buffer. Test compounds are dissolved in DMSO to give a concentration of 10 mg/mL. One μL of this solution is added to each well of a 96 well plate. A mixture of C. elegans in M9 Buffer (100 μL) is added to each well, such that approximately 50 worms of mixed stages (L1, L2, L3, L4 and adults) are present in each well at a final concentration of 100 ppm, 150 ppm or 200 μM of test compound. Concentration of test compound may be varied by gradient dilution of the stock DMSO solution. Observations are made under a dissecting microscope at 4 h and 24 h postimmersion. A rating is based on the motility of the larvae and adults, using the rating system shown below. The results are shown in Table VII, wherein all test compounds are the Z isomer, unless otherwise noted.

TABLE VII

R R1 R2 Dose Rating H 4-biphenyl 4-CF₃—C₆H₄ 150 ppm 9 H 3-CF₃—C₆H₄ 4-(3′-CF₃- 150 ppm 8 biphenyl) H 4-(3-F-biphenyl) 3-CF₃—C₆H₄ 150 ppm 9 H 2-CH₂OH—C₆H₄ 4-(2′-CH₂OH- 150 ppm 0 biphenyl) H 3-N(COCH₃)—C₆H₄ 4-[3′- 150 ppm 0 N(COCH₃)biphenyl] H 4-CN—C₆H₄ 4-(4′-CN-biphenyl) 150 ppm 8 H 3-CH₂OH—C₆H₄ 4-(3′-CH₂OH- 150 ppm 0 biphenyl) H 3,5-diCl—C₆H₃ 4-(3′,5′-diCl- 150 ppm 7 biphenyl) H 4-Cl—C₆H₄ 4-(4′-Cl-biphenyl) 150 ppm 9 H 4(4′-t-bu-biphenyl) 4-biphenyl 150 ppm 0 H 4-biphenyl 4-biphenyl 150 ppm 9 H 1-naphthyl 4-biphenyl 150 ppm 9 H 4-CH₃C₆H₄ 4-(4′-CH₃- 150 ppm 0 biphenyl) H 2-F—C₆H₄ 4-(2′-F-biphenyl) 150 ppm 8 H 3-CN—C₆H₄ 4-(3′-CN-biphenyl) 150 ppm 0 H 2-CH₃—C₆H₄ 4-(2′-CH₃- 150 ppm 8 biphenyl) H 3,5-diCF₃—C₆H₃ 4-(3′,5′-diCF₃- 150 ppm 0 biphenyl) H 2,4-diCl—C₆H₃ 4-biphenyl 150 ppm 9 H 3,4-diCl—C₆H₃ 4-biphenyl 150 ppm 9 H 3,5-diCl—C₆H₃ 4-biphenyl 150 ppm 9 H 3-Cl—C₆H₄ 4-biphenyl 150 ppm 9 H 3,5-diCF₃—C₆H₃ 4-biphenyl 150 ppm 9 H 2-CF₃—C₆H₄ 4-biphenyl 150 ppm 8 H 3,5-diCl—C₆H₃ 4-(3,2′-diOCH₃- 150 ppm 0 biphenyl) H 3-Cl—C₆H₄ 4-(3-OCH₃-2′-Cl- 150 ppm 8 biphenyl) H 3,5-diCl—C₆H₃ 4-(3-OCH₃-2′-Cl- 150 ppm 7 biphenyl) H 3-Cl—C₆H₄ 4-(3-OCH₃-2′-CH₃ 150 ppm 7 biphenyl) H 3-Cl—C₆H₄ 4-(3-CH₃-2′-OCH₃- 150 ppm 7 biphenyl) H 3-5-diCl—C₆H₃ 4-(3-CH₃-2′-OCH₃O 150 ppm 0 H 3-5-diCl—C₆H₃ 4-(3-OCH₃-2′-CH₃- 150 ppm 9 biphenyl) H 3-Cl—C₆H₄ 4-(3-CH₃-2′-CF₃- 150 ppm 9 biphenyl) H 3-5-diCl—C₆H₃ 4-(3-CH₃-2′-CF₃- 150 ppm 0 biphenyl) H 3-Cl—C₆H₄ 4-(3,2′-diCH₃- 150 ppm 9 biphenyl) H 3,5-diCl—C₆H₃ 4-(3-CH₃-2′-Cl- 150 ppm 7 biphenyl) H 3-Cl—C₆H₄ 4-(3-CH₃-2′-Cl- 150 ppm 9 biphenyl) H 3,5-diCl—C₆H₃ 4-(3,2′-diCH₃- 150 ppm 0 biphenyl) H 3,5-diCl—C₆H₃ 4-(3-OCH₃-2′-CF₃- 150 ppm 0 biphenyl) H 3-Cl—C₆H₄ 4-(3-OCH₃-2′-CF₃- 150 ppm 9 biphenyl) H 3,5-diCl—C₆H₃ 4-(3-CH₃-2′- 150 ppm 8 CH₃SO₃- biphenyl) H 4-OCH₃—C₆H₄ 4-biphenyl 150 ppm 9 H 3-CF₃—C₆H₄ C₆H₅ 150 ppm 8 H 4-Cl—C₆H₄ 3-CF₃—C₆H₄ 150 ppm 9 H C₆H₅ 3-CF₃—C₆H₄ 150 ppm 0 H 2-naphthyl 3-CF₃—C₆H₄ 150 ppm 9 H 2-naphthyl 1-naphthyl 150 ppm 9 H 4-biphenyl 4-Cl—C₆H₄ 150 ppm 9 H 4-Cl—C₆H₄ 4-Cl—C₆H₄ 150 ppm 9 H 4-Cl—C₆H₄ 1-naphthyl 150 ppm 9 H 3-CF₃—C₆H₄ 3-CF₃—C₆H₄ 150 ppm 9 H 4-OCH₃—C₆H₄ 2-naphthyl 150 ppm 0 H 4-OCH₃—C₆H₄ 4-OCH₃—C₆H₄ 150 ppm 0 H 4-Cl—C₆H₄ 4-OCH₃—C₆H₄ 150 ppm 0 H 4-OCH₃—C₆H₄ 4-Cl—C₆H₄ 150 ppm 0 H 1-naphthyl 4-Cl—C₆H₄ 150 ppm 0 H 3-CF₃—C₆H₄ 2-naphthyl 150 ppm 9 H 1-naphthyl 1-naphthyl 150 ppm 0 H 1-naphthyl 3-CF₃—C₆H₄ 150 ppm 0 H 3-CF₃—C₆H₄ 4-OCH₃—C₆H₄ 150 ppm 9 H 4-biphenyl 2-CF₃—C₆H₄ 150 ppm 9 H 2-naphthyl 2-naphthyl 150 ppm 9 H 4-biphenyl 2-naphthyl 150 ppm 0 H 4-Cl—C₆H₄ 2-naphthyl 150 ppm 9 H 1-naphthyl 2-naphthyl 150 ppm 9 H 4-(3-F-biphenyl) 2-CF₃—C₆H₄ 150 ppm 9 H 4-COCH₃—C₆H₄ 2-CF₃—C₆H₄ 150 ppm 0 H 4-CN—C₆H₄ 2-CF₃—C₆H₄ 150 ppm 7 H 4-F—C₆H₄ 2-CF₃—C₆H₄ 150 ppm 0 H 3-biphenyl 3-CF₃—C₆H₄ 150 ppm 0 H 3,5-diCl—C₆H₃ 1-naphthyl 150 ppm 9 H 4-CF₃—C₆H₄ 1-naphthyl 150 ppm 9 H 3-COCH₃—C₆H₄ 1-naphthyl 150 ppm 8 H 4-(CH₃C═NOH)—C₆H₄ 1-naphthyl 150 ppm 7 H 4-CO₂CH₃—C₆H₄ 1-naphthyl 150 ppm 9 H 3,4-diCl—C₆H₃ 4-(3′,4′-diCl- 150 ppm 9 biphenyl) H 3-CHO—C₆H₄ 1-naphthyl 150 ppm 0 H 3-CH₂OH—C₆H₄ 1-naphthyl 150 ppm 0 H 3-(C═NOH)—C₆H₄ 1-naphthyl 150 ppm 0 H 4-(3-F-biphenyl) 4-Cl—C₆H₄ 150 ppm 9 H 4-Cl—C₆H₄ 2-(4′-Cl-biphenyl) 150 ppm 0 H 4-(3-F-biphenyl) 3,5-diCl—C₆H₃ 150 ppm 9 H 3-Cl—C₆H₄ 2-(3′-Cl-biphenyl) 150 ppm 0 H 3-F-4-(1-morpho- 2-Cl-5-CF₃—C₆H₃ 150 ppm 0 lino)-C₆H₄ H 4-Cl—C₆H₄ 1-[(4- 150 ppm 0 dimethylamino)- naphthyl] H 3,5-diClC₆H₃ 1-[(4- 150 ppm 0 dimethylamino)- naphthyl] H 4-CF₃—C₆H₄ 1-[(4- 150 ppm 0 dimethylamino)- naphthyl] H 3-Cl—C₆H₄ 3-F-4-[1-(4- 150 ppm 7 CO₂C₂H₅- piperazinyl)]-C₆H₃ H 4-CN—C₆H₄** 4-(4′-Cl-biphenyl) 150 ppm 9 H 4-Cl—C₆H₄ 4-(4′-CN-biphenyl) 150 ppm 9 H 4-Cl—C₆H₄* 4-(4′-CN-biphenyl) 150 ppm 9 H 4-Cl—C₆H₄** 4-CN—C₆H₄ 150 ppm 9 H 4-Cl—C₆H₄** 3-Cl—C₆H₄ 150 ppm 9 H 3-CF₃—C₆H₄ 4-Cl—C₆H₄ 100 ppm 9 CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 100 ppm 0 CO₂t-Bu 4-Cl—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 CO₂C₆H₅ 4-Cl—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 CO₂CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 CH₂CH═CH₂ 4-Cl—C₆H₄** 4-CN—C₆H₄ 100 ppm 0 H 4-CF₃—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 H 4-CF₃—C₆H₄** 4-Cl—C₆H₄ 100 ppm 9 H 4-CF₃—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H 4-CF₃—C₆H₄** 4-(4′-Cl-biphenyl) 100 ppm 9 H 4-CF₃—C₆H₄** 4-(4′-CN-biphenyl) 100 ppm 9 H 4-CF₃—C₆H₄** 4-F—C₆H₄ 100 ppm 9 H 4-F—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 H 4-F—C₆H₄** 4-Cl—C₆H₄ 100 ppm 9 H 4-F—C₆H₄* 4-CF₃—C₆H₄ 100 ppm 9 H 4-F—C₆H₄** 4-F—C₆H₄ 100 ppm 9 H 4-F—C₆H₄ 4-(4′-CN-biphenyl) 100 ppm 9 H 4-F—C₆H₄** 4-(4′-Cl-biphenyl) 100 ppm 9 H 3-Cl—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 H 3-Cl—C₆H₄** 4-Cl—C₆H₄ 100 ppm 9 H 3-Cl—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H 3-Cl—C₆H₄** 4-(4′-Cl-biphenyl) 100 ppm 9 H 3-Cl—C₆H₄** 4-(4′-CN-bipehnyl) 100 ppm 9 H 3-Cl—C₆H₄** 4-F—C₆H₄ 100 ppm 9 H 3-CF₃—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 H 3-CF₃—C₆H₄** 4-F—C₆H₄ 100 ppm 9 H 3-CF₃—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H 3-CF₃—C₆H₄** 4-(4′-Cl-biphenyl) 100 ppm 9 H 3-CF₃—C₆H₄** 4-(4′-CN-biphenyl) 100 ppm 9 H 3-CN—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 H 3-CN—C₆H₄** 4-Cl—C₆H₄ 100 ppm 9 H 3-CN—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H 3-CN—C₆H₄** 4-(4′-Cl-biphenyl) 100 ppm 9 H 3-CN—C₆H₄** 4-(4′-CN-biphenyl) 100 ppm 9 H 3-CN—C₆H₄** 4-F—C₆H₄ 100 ppm 7 H 4-CN—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 3-CF₃—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 4-(4′-CF₃- 100 ppm 9 biphenyl) H 4-CN—C₆H₄** 4-F—C₆H₄ 100 ppm 9 H 4-Cl—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H 4-Cl—C₆H₄** 2-CF₃—C₆H₄ 100 ppm 9 H 4-Cl—C₆H₄** 4-(4′-CF₃-biphenyl) 100 ppm 9 H 4-Cl—C₆H₄** 4-F—C₆H₄ 100 ppm 9 H 4-(4′-Cl-biphenyl)** 4-CF₃—C₆H₄ 100 ppm 9 H 4-(4′-Cl-biphenyl)** 4-CN—C₆H₄ 100 ppm 9 H 4-(4′-Cl-biphenyl)** 4-Cl—C₆H₄ 100 ppm 9 H 4-(4′-CN-biphenyl)** 4-CF₃—C₆H₄ 100 ppm 9 H 4-(4′-CN-biphenyl)** 4-CN—C₆H₄ 100 ppm 9 H 4-(4′-CN-biphenyl)** 4-Cl—C₆H₄ 100 ppm 9 H 4-Cl—C₆H₄** 3,4-diCl—C₆H₄ 100 ppm 9 H 4-Cl—C₆H₄** 2,4-diCl—C₆H₄ 100 ppm 9 H 4-Cl—C₆H₄** 3-F-4-CF₃—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 3,4-diCl—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 2,4-diCl—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 3-F-4-CF₃—C₆H₄ 100 ppm 9 CH₃ 3-CF₃—C₆H₄ 3-CF₃—C₆H₄ 150 ppm 0 CH₃ 4-OCH₃—C₆H₄ C₆H₅ 150 ppm 0 CH₃ 4-OCH₃—C₆H₄ 3-CF₃—C₆H₄ 150 ppm 0 CH₃ 3-CF₃—C₆H₄ C₆H₅ 150 ppm 0 CH₃ 4-Cl—C₆H₄ C₆H₅ 150 ppm 0 CH₃ C₆H₅ 3-CF₃—C₆H₄ 150 ppm 0 H 4-biphenyl 3-F-5-CF₃—C₆H₃ 200 μM 9 H 4-(3-F-biphenyl) 3-F-5-CF₃—C₆H₃ 200 μM 9 H 4-(4′-nBu-biphenyl) 3-F-5-CF₃—C₆H₃ 200 μM 9 H 3-biphenyl 3-F-5-CF₃—C₆H₃ 200 μM 9 H 4-(2-F-biphenyl) 2-Cl-3-CF₃—C₆H₃ 200 μM 9 H 4-(4′-nPr-biphenyl) 2-Cl-3-CF₃—C₆H₃ 200 μM 9 H 4-(4′-nBu-biphenyl) 2-Cl-3-CF₃—C₆H₃ 200 μM 9 H 4-(4′-nPr-biphenyl) 2-F-5-CF₃—C₆H₃ 200 μM 9 H 4-(4′-nBu-biphenyl) 2-F-5-CF₃—C₆H₃ 200 μM 0 H 3-biphenyl 2-F-5-CF₃—C₆H₃ 200 μM 9 H 4-(4′-OC₂H₅-biphenyl) 2-F-5-CF₃—C₆H₃ 200 μM 9 H 4-biphenyl 2-Cl-5-CF₃—C₆H₃ 200 μM 9 H 4-(4′-nPr-biphenyl) 2-Cl-5-CF₃—C₆H₃ 200 μM 0 H 4-(4′-tBu-biphenyl) 3-CF₃—C₆H₄ 200 μM 0 H 3-isopropyl-C₆H₄ 2-Cl-5-CF₃—C₆H₃ 200 μM 0 H 4-(C₂H₅)—C₆H₄ 2-Cl-5-CF₃—C₆H₃ 200 μM 9 H 4-CH₃—C₆H₄ 2-Cl-5-CF₃—C₆H₃ 200 μM 0 H 2,3-di-CH₃—C₆H₃ 2-Cl-5-CF₃—C₆H₃ 200 μM 0 H 3,4-di-CH₃—C₆H₃ 2-Cl-5-CF₃—C₆H₃ 200 μM 0 H 3,5-di-CH₃—C₆H₃ 2-Cl-5-CF₃—C₆H₃ 200 μM 0 H 2,5-di-CH₃—C₆H₃ 2-Cl-5-CF₃—C₆H₃ 200 μM 0 H 4-isopropyl-C₆H₄ 2-Cl-3-CF₃—C₆H₃ 200 μM 9 H 4-CH₃—C₆H₄ 2-Cl-3-CF₃—C₆H₃ 200 μM 9 H 3,4-di-CH₃—C₆H₃ 2-Cl-3-CF₃—C₆H₃ 200 μM 9 H 4-biphenyl 3-CF₃—C₆H₄ 200 μM 9 H 3,5-diCl—C₆H₃ 3-F-4-[1-(4- 150 ppm 0 CO₂C₂H₅- piperazinyl)]-C₆H₃ H 3-Cl—C₆H₄ 1-(4-OCH₃- 150 ppm 9 naphthyl) H 3,5-diCl—C₆H₃ 1-(4-OCH₃- 150 ppm 0 naphthyl) H 3-Cl—C₆H₄ 1-[4-(N-morpholino)- 150 ppm 0 naphthyl)] H 3,5-diCl—C₆H₃ 1-[4-(N-morpholino)- 150 ppm 0 naphthyl)] H 3,5-diCl—C₆H₃ 3-(benzyloxy)-C₆H₄ 150 ppm 0 H 3,5-diCl—C₆H₃ 2-(benzyloxy)-C₆H₄ 150 ppm 0 H 3,5-diCl—C₆H₃ 3-Cl-4-{1-[4-(2-Cl—C₆H₄)- 150 ppm 0 piperazinyl)}-C₆H₃ H 3,5-diCl—C₆H₃ 3- 150 ppm 0 (CONHCH₂CONHCH₂—CO₂C₂H₅)—C₆H₄ H 3,5-diCl—C₆H₃ 3- 150 ppm 0 (CONHCH₂CONHCH₂—CO2C₂H₅)—C₆H₄ H 3,5-diCl—C₆H₃ 4-(3-CH₃-2-COCH₃- 150 ppm 0 biphenyl) H 4-CN—C₆H₄* 4-(4′-CN-biphenyl) 150 ppm 9 H 4-CN—C₆H₄** 4-Cl—C₆H₄ 150 ppm 9 H 4-CN—C₆H₄** 4-CN—C₆H₄ 150 ppm 9 H 4-F—C₆₄** 4-OCF₃—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 4-OCF₃—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 4-OCHF₂—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 4-OCF₂CHF₂—C₆H₄ 100 ppm 9 H 4-CN—C₆H₄** 5-chlorothiophen-2- 100 ppm 9 yl H 4-CN—C₆H₄** 2,2difluoro-1,3- 100 ppm 9 dioxol- C₆H₃-5-yl H 4-OCF₃—C₆H₄** 3,5-diCl—C₆H₃ 100 ppm 9 H 4-OCF₃—C₆H₄** 3,4-diF—C₆H₃ 100 ppm 9 H 4-OCF₃—C₆H₄** 4-n-propoxy-C₆H₄ 100 ppm 0 H 4-OCF₃—C₆H₄** 3,4-diCl—C₆H₃ 100 ppm 9 H 4-OCF₃—C₆H₄** 3-F-4-CF₃—C₆H₃ 100 ppm 9 H 4-OCF₃—C₆H₄** 5-chlorothiophen-2- 100 ppm 9 yl H 4-OCF₃—C₆H₄** thiophen-2-yl 100 ppm 0 H 4-OCF₃—C₆H₄** 4-phenoxy-C₆H₄ 100 ppm 0 H 4-OCF₃—C₆H₄** pyridine-3-yl 100 ppm 0 H 4-OCF₃—C₆H₄** 4-OCF₃—C₆H₄ 100 ppm 9 H 4-OCF₃—C₆H₄** 4-F—C₆H₄ 100 ppm 9 H 4-OCF₃—C₆H₄** 4-CN—C₆H₄ 100 ppm 9 H 4-OCF₃—C₆H₄** 4-Cl—C₆H₄ 100 ppm 9 H 4-OCF₃—C₆H₄** 4-OCHF₂—C₆H₄ 100 ppm 9 H 4-OCF₃—C₆H₄** 2-F-5-CF₃—C₆H₃ 100 ppm 9 H 4-OCF₃—C₆H₄** 4-CF₃—C₆H₄ 100 ppm 9 H 4-OCF₃—C₆H₄** 3-F-5-CF₃—C₆H₃ 100 ppm 9 H 4-OCF₃—C₆H₄** 2-F-4-CF₃—C₆H₃ 100 ppm 9 H 4-OCF₃—C₆H₄** 4-OCF₂CHF₂—C₆H₄ 100 ppm 9 H 4-OCF₃—C₆H₄** 2,2difluoro-1,3- 100 ppm 9 dioxol- C₆H₃-5-yl H 4-OCF₃—C₆H₄** pyridine-4-yl 100 ppm 0 H 4-OCF₃—C₆H₄** pyridine-2-yl 100 ppm 0 H 4-OCF₃—C₆ ₄** 3-Br-pyridine-2-yl 100 ppm 0 H 4-OCF₃—C₆H₄** 4-(4-F-phenyl)- 100 ppm 9 pyridin-3-yl H 4-OCF₃—C₆H₄** 4-(thiophen-2-yl)- 100 ppm 9 pyridin-3-yl H 4-OCF₃—C₆H₄** 4-(4-OCF₃- 100 ppm 9 phenyl)- pyridin3-yl H 4-OCF₃—C₆H₄** 4-(5-Cl-thiophen-2- 100 ppm 9 yl)- pyridin-3-yl H 4-OCF₃—C₆H₄** 4-(4-Cl-phenyl)-pyridin- 100 ppm 9 3-yl H 4-OCF₃—C₆H₄** 4-(3-Cl-phenyl)-pyridin- 100 ppm 9 3-yl H 4-OCF₃—C₆H₄** 4-Br-pyridine-3-yl 100 ppm 9 H 4-OCF₃—C₆H₄** 3-Cl-pyridine-4-yl 100 ppm 9 H 4-OCF₃—C₆H₄** 4-cyclopropylmethoxy- 100 ppm 0 C₆H₄ H 4-OCF₃—C₆H₄** 4-(5-Cl-thiophen-2-yl)- 100 ppm 9 C₆H₄ H 4-OCF₃—C₆H₄** 2-methyl-1H- 100 ppm 0 imidazol-4-yl H 4-OCF₃—C₆H₄** 5-chloro-1,3- 100 ppm 0 dimethyl- 1H-pyrazol-4-yl H 4-OCF₃—C₆H₄** 5-methyl-1-o-tolyl- 100 ppm 0 1H- pyrazol-4-yl H 4-OCF₃—C₆H₄** 2-phenyl-1H- 100 ppm 0 imdiazol-4-yl H 4-OCF₃—C₆H₄** 2-Cl-pyridine-3-yl 100 ppm 9 H 4-OCF₃—C₆H₄** 4-chloro-1-methyl- 100 ppm 0 1H- pyrazol-3-yl H 4-OCF₃—C₆H₄** 5-(4-F-3-CF₃- 100 ppm 9 phenyl)- furan-2-yl H 4-OCF₃—C₆H₄** 5-chloro-1-methyl- 100 ppm 0 3- trifluoromethyl-1H- imidazol-3-yl H 4-OCF₃—C₆H₄** 5-bromo-1-methyl- 100 ppm 0 1H- imidazol-3-yl H 4-OCF₃—C₆H₄** 1-(4-methoxyphenyl)- 100 ppm 0 5- methyl-1H-pyrazol-4- yl H 4-OCF₃—C₆H₄** 1-(4-fluorophenyl)-5- 100 ppm 0 methyl-1H-pyrazol-4- yl H 4-OCF₃—C₆H₄** 1-(phenyl)-5-methyl- 100 ppm 0 1H- pyraozl-4-yl H 4-OCF₃—C₆H₄** 2-methanesulfanyl- 100 ppm 9 nicotinonitrile H 4-OCF₃—C₆H₄** 5-bromo-furan-2-yl 100 ppm 9 H 4-OCF₃—C₆H₄** 6-phenoxy-pyridin- 100 ppm 9 3-yl H 4-OCF₃—C₆H₄** 4-(1,2,4-triazol-1- 100 ppm 9 yl)- C₆H₄ H 4-OCF₃—C₆H₄** 5-(pyridine-2-yl)- 100 ppm 9 thiphen-2-yl H 4-OCF₃—C₆H₄** 5-(6-morpholin-4- 100 ppm 0 yl)- pyridin-3-yl H 4-OCF₃—C₆H₄** 4-(4-methyl- 100 ppm 0 piperazin-1- yl)-C₆H₄ H 4-OCF₃—C₆H₄** 4-(thiophen-2-yl)- 100 ppm 9 C₆H₄ H 4-OCF₃—C₆H₄** 4-(pyrrol-1-yl)- 100 ppm 9 C₆H₄ H 4-OCF₃—C₆H₄** 4-(4′-Cl-biphenyl) 100 ppm 9 H 4-OCF₃—C₆H₄** 4-(4′-CN-biphenyl) 100 ppm 9 H 4-OCF₃—C₆H₄** 2,5-dimethyl-2H- 100 ppm 0 pyrazol-3-yl H thiophen-2-yl 4-CN—C₆H₄ 100 ppm 0 H thiophen-2-yl 4-Cl—C₆H₄ 100 ppm 7 H thiophen-2-yl 4-CF₃—C₆H₄ 100 ppm 7 H 5-chlorothiophen-2-yl 4-Cl—C₆H₄ 100 ppm 9 H 5-chlorothiophen-2-yl 4-CN—C₆H₄ 100 ppm 9 H 5-chlorohtiophen-2-yl 4-CF₃—C₆H₄ 100 ppm 9 H 5-chlorothiophen-2-yl 4-OCF₃—C₆H₄ 100 ppm 9 H 5-chlorothiophen-2-yl 4-OCHF₂—C₆H₄ 100 ppm 9 H 5-chlorothiophen-2-yl 3,4-diCl—C₆H₃ 100 ppm 9 H 5-chlorothiophen-2-yl 3,4-diF—C₆H₃ 100 ppm 9 H 5-chlorothiophen-2-yl 4-F-3-CF₃—C₆H₃ 100 ppm 9 H 5-chlorothiophen-2-yl 4-F—C₆H₄ 100 ppm 9 H 5-chlorothiophen-2-yl 4-cyclopropylmethoxy- 100 ppm 9 C₆H₄ H 5-chlorothiophen-2-yl 5-chlorothiophen-2- 100 ppm 9 yl H 4-Cl—C₆H₄** 4-cyclopropylmethoxy- 100 ppm 7 C₆H₄ H 4-Cl—C₆H₄** 4-SCF₃—C₆H₄ 100 ppm 9 Rating Description 0 no effect 7 reduced movement in 24 h 8 dead in 24 h 9 dead in 4 h *E isomer **Mixture of Z and E isomers

Example 327 In Vivo Evaluation of the Efficacy of Test Compounds Against T. colubriformis

In this evaluation, gerbils are infected with Trichostrongylus columbriformis infective larvae at a concentration of approximately 800 L₃/mL. Larvae for gerbil infections are cultured from feces from sheep previously infected with T. colubriformis. One week post infection, test compounds are administered by gavage as a single oral dose of 50 mg/kg of body weight. For each group of 3 gerbils, 10 mg of test compound are dissolved in 2 mL of PEG 400:DMSO (1:2 v/v) and each animal is administered the test solution at a rate of 0.1 mL/10 g of body weight. Treatments are randomly allocated to groups of 3 infected gerbils each; 35 groups are treated with test compounds; 4 groups are untreated (administered vehicle only) as a negative control; and one group is treated with a known endectoside, NEMADECTIN as a positive control. All animals are observed daily for morbidity and mortality. Four days post-treatment, all animals are weighed and necropsied. Worm counts are conducted with the use of stereoscopes and counters. The results are recorded as % mortality as compared to that of the negative control for the worms. Toxicity is indicated for those groups having one or more animals expired or demonstrating significant weight loss as compared to the negative control. The data are shown in Table VIII, wherein all test compounds are the Z isomer, unless otherwise noted.

TABLE VIII

R R1 R2 Mortality Toxicity H 4-biphenyl 4-CF₃—C₆H₄ 0.00 − H 4-(3-F-biphenyl) 3-CF₃—C₆H₄ 20.60 − H 4-CN—C₆H₄ 4-(4′CN-biphenyl) 88.60 + H 4-Cl—C₆H₄ 4-(4′-Cl-biphenyl) 61.33 + H 4-Cl—C₆H₄ 4-biphenyl 33.10 + H 1-naphthyl 4-biphenyl 18.50 − H 2-F—C₆H₄ 4-(2′F-biphenyl) 12.40 − H 2-CH₃—C₆H₄ 4-(2′-CH₃-biphenyl) 21.30 − H 2,4-diCl—C₆H₃ 4-biphenyl 24.50 − H 3,5-diCl—C₆H₃ 4-biphenyl 52.60 + H 3-Cl—C₆H₄ 4-biphenyl 19.40 − H 3,5-diCF₃—C₆H₃ 4-biphenyl 60.80 + H 2-CF₃—C₆H₄ 4-biphenyl 20.20 − H 3-Cl—C₆H₄ 4-(3-OCH₃-2′-Cl-biphenyl) 0.00 − H 3-Cl—C₆H₄ 4-(3-CH₃-2′-OCH₃-biphenyl 0.00 − H 3-Cl—C₆H₄ 4-(3-CH₃-2′-CF₃-biphenyl 11.20 − H 3-Cl—C₆H₄ 4-(3,2′-diCH₃-biphenyl) 10.80 − H 3-Cl—C₆H₄ 4-(3-CH₃-2′-Cl-biphenyl) 16.90 − H 3-Cl—C₆H₄ 4-(3-OCH₃-2′-CF₃-biphenyl) 29.50 + H 4-OCH₃—C₆H₄ 4-biphenyl 44.90 − H 4-(3-F-biphenyl) 4-(3-F-biphenyl) 17.00 − H 3-CF₃—C₆H₄ 2-naphthyl 35.20 − H 2-naphthyl 1-naphthyl 36.10 − H 4-Cl—C₆H₄ 4-Cl—C₆H₄ 79.78 + H 4-Cl—C₆H₄ 4-Cl—C₆H₄ 79.78 + H 3-CF₃—C₆H₄ 3-CF₃—C₆H₄ 10.10 − H 4-Cl—C₆H₄ 4-OCH₃—C₆H₄ 7.10 — H 3-CF₃—C₆H₄ 4-OCH₃—C₆H₄ 3.10 − H 4-biphenyl 2-CF₃—C₆H₄ 23.90 − H 2-naphthyl 2-naphthyl 13.80 − H 4-Cl—C₆H₄ 2-naphthyl 52.80 − H 1-naphthyl 2-naphthyl 28.90 − H 4-(3-F-biphenyl) 2-CF₃—C₆H₄ 51.60 − H 4-CN—C₆H₄ 2-CF₃—C₆H₄ 69.78 − H 3,5-diCl—C₆H₃ 1-naphthyl 0.00 − H 3-COCH₃—C₆H₄ 1-naphthyl 10.70 — H 3,4-diCl—C₆H₃ 4-(3′,4′-diCl-biphenyl) 22.00 − H 4-(3-F-biphenyl) 4-Cl—C₆H₄ 22.00 − H 4-CN—C₆H₄* 4-(4′-CN-biphenyl) 88.07 − H 4-CN—C₆H₄ 4-Cl—C₆H₄ 90.20 + H 4-CN—C₆H₄ 4-CN—C₆H₄ 62.43 + H 4-CN—C₆H₄ 4-(4′-Cl-biphenyl) 64.33 + H 4-Cl—C₆H₄ 4-(4′-CN-biphenyl) 48.90 + H 4-Cl—C₆H₄* 4-(4′-CN-biphenyl) 23.80 − H 4-Cl—C₆H₄ 4-CN—C₆H₄ 84.54 + H 4-Cl—C₆H₄ 3-Cl—C₆H₄ 25.40 − H 3,4-diCl—C₆H₃ 4-biphenyl 23.00 − H 3,5-diCl—C₆H₃ 4-(3-OCH₃-2′-Cl-biphenyl) 41.00 − H 3-biphenyl 3-F-5-CF₃—C₆H₄ 0.00 − H 3-biphenyl 2-F-5-CF₃—C₆H₄ 38.40 − H 4-biphenyl 2-Cl-5-CF₃—C₆H₄ 38.40 − H 4-(C₂H₅)—C₆H₄ 2-Cl-5-CF₃—C₆H₄ 39.00 − H 3,4-diCH₃—C₆H₃ 2-Cl-3-CF₃—C₆H₄ 36.50 − H 2-CF₃—C₆H₄ C₆H₅ 34.60 − H 4-biphenyl 4-Cl—C₆H₄ 44.70 − H 4-Cl—C₆H₄ 1-naphthyl 0.00 − H 3-CF₃—C₆H₄ 4-Cl—C₆H₄ 21.60 − CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 0.00 − CO₂tBu 4-Cl—C₆H₄** 4-CN—C₆H₄ 0.00 − CO₂C₆H₅ 4-Cl—C₆H₄** 4-CN—C₆H₄ 0.00 − CO₂CH₃ 4-Cl—C₆H₄** 4-CN—C₆H₄ 96.90 − CH₂CH═CH₂ 4-Cl—C₆H₄** 4-CN—C₆H₄ 0.00 — H 4-CF₃—C₆H₄ 4-(4′-CN-biphenyl) 91.50 − H 4-CF₃—C₆H₄** 4-F—C₆H₄ 95.80 + H 4-F—C₆H₄** 4-CN—C₆H₄ 14.70 − H 4-F—C₆H₄** 4-Cl-C₆H₄ 0.00 − H 4-F—C₆H₄** 4-CF₃—C₆H₄ 25.60 − H 4-F—C₆H₄** 4-F—C₆H₄ 0.00 − H 4-F—C₆H₄ 4-(4′-CN-biphenyl) 31.80 − H 4-F—C₆H₄** 4-(4′-Cl-biphenyl) 1.60 − H 3-Cl—C₆H₄** 4-CN—C₆H₄ 43.70 − H 3-Cl—C₆H₄** 4-Cl—C₆H₄ 18.80 − H 3-Cl—C₆H₄** 4-CF₃—C₆H₄ 57.90 − H 3-Cl—C₆H₄** 4-(4′-Cl-biphenyl) 37.60 − H 3-Cl—C₆H₄** 4-(4′-CN-biphenyl) 32.00 − H 3-Cl—C₆H₄** 4-F—C₆H₄ 3.00 − H 3-CF₃—C₆H₄** 4-CN—C₆H₄ 0.00 − H 3-CF₃—C₆H₄** 4-F—C₆H₄ 36.40 − H 3-CF₃—C₆H₄** 4-CF₃—C₆H₄ 0.00 − H 3-CF₃—C₆H₄** 4-(4′-Cl-biphenyl) 31.30 − H 3-CF₃—C₆H₄** 4-(4′-CN-biphenyl) 47.50 − H 3-CN—C₆H₄** 4-CN—C₆H₄ 25.50 − H 3-CN—C₆H₄** 4-Cl—C₆H₄ 0.00 − H 3-CN—C₆H₄** 4-CF₃—C₆H₄ 0.00 − H 3-CN—C₆H₄** 4-(4′-Cl-biphenyl) 0.00 — H 3-CN—C₆H₄** 4-(4′-CN-biphenyl) 30.30 − H 3-CN—C₆H₄** 4-F—C₆H₄ 0.00 − H 4-CN—C₆H₄** 3-CF₃—C₆H₄ 50.00 − H 4-CN—C₆H₄** 4-F—C₆H₄ 82.10 − H 4-Cl—C₆H₄** 4-(4′_CF₃-biphenyl) 0.00 − H 4-Cl—C₆H₄** 4-F—C₆H₄ 72.60 + H 4-(4′-Cl-biphenyl)** 4-CF₃—C₆H₄ 21.30 − H 4-(4′-Cl-biphenyl)** 4-CN—C₆H₄ 0.00 − H 4-(4′-Cl-biphenyl)** 4-Cl—C₆H₄ 0.00 − H 4-(4′-CN- 4-CF₃—C₆H₄ 24.90 − biphenyl)** H 4-(4′-CN- 4-CN—C₆H₄ 29.80 − biphenyl)** H 4-(4′-CN- 4-Cl—C₆H₄ 13.10 − biphenyl)** H 4-Cl—C₆H₄** 3,4-diCl—C₆H₄ 58.0 − H 4-Cl—C₆H₄** 2,4-diCl—C₆H₄ 91.40 − H 4-F—C₆H₄** 4-OCF₃—C₆H₄ 51.60 − H 4-CN—C₆H₄** 4-OCF₃—C₆H₄ 90.00 + H 4-CN—C₆H₄** 4-OCHF₂—C₆H₄ 48.40 − H 4-CN—C₆H₄** 4-OCF₂CHF₂—C₆H₄ 92.80 − H 4-CN—C₆H₄** 5-chlorothiophen-2-yl 20.60 − H 4-CN—C₆H₄** 2,2difluoro-1,3-dioxol- 88.10 − C₆H₃-5-yl H 4-OCF₃—C₆H₄** 3,5-diCl—C₆H₃ 33.40 − H 4-OCF₃—C₆H₄** 3,4-diF—C₆H₃ 100.0 + H 4-OCF₃—C₆H₄** 4-n-propoxy-C₆H₄ 10.40 − H 4-OCF₃—C₆H₄** 3,4-diCl—C₆H₃ 100.0 + H 4-OCF₃—C₆H₄** 3-F-4-CF₃—C₆H₃ 44.20 − H 4-OCF₃—C₆H₄** 5-chlorothiophen-2-yl 26.10 − H 4-OCF₃—C₆H₄** thiophen-2-yl 0.00 − H 4-OCF₃—C₆H₄** 4-phenoxy-C₆H₄ 0.00 − H 4-OCF₃—C₆H₄** pyridine-3-yl 0.00 − H 4-OCF₃—C₆H₄** 4-OCF₃—C₆H₄ 100.0 + H 4-OCF₃—C₆H₄** 4-F—C₆H₄ 0.00 + H 4-OCF₃—C₆H₄** 4-CN—C₆H₄ 88.90 + H 4-OCF₃—C₆H₄** 4-Cl—C₆H₄ 100.0 + H 4-OCF₃—C₆H₄** 4-OCHF₂—C₆H₄ 44.20 − H 4-OCF₃—C₆H₄** 2-F-5-CF₃—C₆H₃ 29.50 − H 4-OCF₃—C₆H₄** 4-CF₃—C₆H₄ 55.50 + H 4-OCF₃—C₆H₄** 3-F-5-CF₃—C₆H₃ 42.90 − H 4-OCF₃—C₆H₄** 2-F-4-CF₃—C₆H₃ 100.0 + H 4-OCF₃—C₆H₄** 4-OCF₂CHF₂—C₆H₄ 47.10 − H 4-OCF₃—C₆H₄** 2,2difluoro-1,3-dioxol- 27.70 + C₆H₃-5-yl H 4-OCF₃—C₆H₄** pyridine-4-yl 0.00 − H 4-OCF₃—C₆H₄** pyridine-2-yl 0.00 − H 4-OCF₃—C₆H₄** 3-Br-pyridine-2-yl 26.90 − H 4-OCF₃—C₆H₄** 4-(4-F-phenyl)-pyridin-3-yl 12.80 − H 4-OCF₃—C₆H₄** 4-(thiophen-2-yl)- 12.80 − pyridin-3-yl H 4-OCF₃—C₆H₄** 4-(4-OCF₃-phenyl)- 82.60 − pyridin-3-yl H 4-OCF₃—C₆H₄** 4-(5-Cl-thiophen-2-yl)- 88.50 − pyridin-3-yl H 4-OCF₃—C₆H₄** 4-(4-Cl-phenyl)- 84.60 − pyridin-3-yl H 4-OCF₃—C₆H₄** 4-(3-Cl-phenyl)- 66.80 − pyridin-3-yl H 4-OCF₃—C₆H₄** 4-Br-pyridine-3-yl 12.80 − *E isomer **Mixture of Z and E isomers 

1. A compound of formula I

wherein R is H; R₁ is phenyl optionally substituted with one, two or three halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally substituted, biphenyl optionally substituted with one, two or three halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally substituted, naphthyl optionally substituted with one, two or three halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally substituted, or heteroaryl optionally substituted with one, two or three halogen, CN, OR₃, COR₄, SO₂R₅, NR₆SO₂R₇, NR₈COR₉, NR₁₀R₁₁, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally substituted; R₂ is phenyl substituted with one optionally substituted heteroaryl group; biphenyl optionally substituted with one, two or three halogen, CN, OR₁₂, COR₁₃, SO₂R₁₄, NR₁₅SO₂R₁₆, NR₁₇COR₁₈, NR₁₉R₂₀, C₁-C₆haloalkyl or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl or C₂-C₆alkynyl group each optionally substituted; heteroaryl substituted with one phenyl or heteroaryl group each optionally substituted; R₃, R₄, R₉, R₁₂, R₁₃ and R₁₈ are each independently H, C₁-C₆, haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally substituted; R₅, R₇, R₁₄ and R₁₆ are each independently a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkyl, benzyl, aryl or heteroaryl group each optionally substituted; R₆, R₈, R₁₅ and R₁₇ are each independently H or an optionally substituted C₁-C₆alkyl group; and R₁₀, R₁₁, R₁₉ and R₂₀ are each independently H, C₁-C₆, haloalkyl, or a C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, benzyl, aryl or heteroaryl group each optionally substituted or R₁₀ and R₁₁ or R₁₉ and R₂₀ may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two additional heteroatoms selected from N, O or S; or the stereoisomers thereof, the tautomers thereof or the pharmaceutically acceptable salts thereof.
 2. The compound according to claim 1 wherein R₂ is an optionally substituted biphenyl group.
 3. The compound according to claim 1 wherein R₁ is phenyl substituted with one or two halogen or C₁-C₆haloalkyl groups.
 4. The compound according to claim 1 wherein R₁ is an optionally substituted biphenyl group.
 5. The compound according to claim 2 wherein R₁ is an optionally substituted phenyl group.
 6. The compound according to claim 3 wherein R₂ is a biphenyl group optionally substituted with one or two halogen, OR₁₂, COR₁₃, C₁-C₆haloalkyl or C₁-C₆alkyl groups.
 7. The compound according to claim 4 wherein R₁ is a biphenyl group substituted with one or two halogen.
 8. The compound according to claim 1 wherein R₂ comprises a pyridyl or furanyl group.
 9. The compound according to claim 1 selected from the group consisting of: (5Z)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)methylene]-3-(3,5-dichlorophenyl)-4-hydroxyfuran-2(5H)-one; (5Z)-5-[(3′,4′-dichloro-1,1′-biphenyl-2-yl)methylene]-3-(3,4-dichlorophenyl)-4-hydroxyfuran-2(5H)-one; 5-[(Z)-[1,1′biphenyl]-4-ylmethylidene]-3-(3-chlorophenyl)-4-hydroxy-2(5H)-furanone; (5E)-5-[2′-chloro-2-methyl-1,1′-biphenyl-4-yl)methylene]-3-(3,5-dichloro-phenyl)-4-hydroxyfuran-2(5H)-one; (5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-{[2-methoxy-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methylene}furan-2(5H)-one; (5Z)-3-(3,5-dichlorophenyl)-5-[2,2′-dimethyl-1,1′-biphenyl-4-yl)methylene]-4-hydroxyfuran-2(5H)-one; 5-{[2-chloro-3-(trifluoromethyl)phenyl]methylene}-3-(3-fluoro-4-biphenyl)-4-hydroxyfuran-2(5H)-one; 3-(3-fluoro-4-biphenyl)-5-{[2-fluoro-5-(trifluoromethyl)phenyl]methylene}-4-hydroxyfuran-2(5H)-one; (5Z)-3-(3,5-dichlorophenyl)-4-hydroxy-5-{[2-methyl-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methylene}furan-2(5H)-one; (5Z)-5-[(2′-acetyl-2-methyl-1,1′-biphenyl-4-yl)methylene]-3-(3,5-dichloro-phenyl)-4-hydroxyfuran-2(5H)-one; 5-[(Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-(3,4-dichlorophenyl)-4-hydroxy-2(5H)-furanone; 5-(Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-(3,5-dichlorophenyl)-4-hydroxy-2(5H)-furanone; 3-(2-fluoro[1,1′-biphenyl]-4-yl)-4-hydroxy-5-{(Z)-[3-(trifluoromethyl)phenyl]-methylidene}furan-2(5H)-one; 5-[(Z)-[1,1′-biphenyl]-4-ylmethylidene]-3-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxy-2(5H)-furanone; 5-{[2-chloro-5-(trifluoromethyl)phenyl]methylene}-3-(3-fluoro-4-biphenyl)-4-hydroxyfuran-2(5H)-one; 5-{[2-chloro-5-(trifluoromethyl)phenyl]methylene}-3-(4′-ethoxy-4-biphenyl)-4-hydroxyfuran-2(5H)-one; (5Z)-3-(3-chlorophenyl)-4-hydroxy-5-{[2-methyl-2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]methylene]furan-2(5H)-one; and (5Z)-5-[(3′-4′-dichloro-1,1′-biphenyl-3-yl)methylene]-3-(3,4-dichlorophenyl)-4-hydroxyfuran-2(5H)-one; or the stereoisomers thereof; the tautomers thereof; or the pharmaceutically acceptable salts thereof.
 10. A method for the control of nematode pests or parasites which comprises contacting said pests or parasites, their food supply, habitat or breeding ground with a pesticidally or parasiticidally effective amount of a compound of formula I according to claim 1; or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof.
 11. A method for the protection of a growing or harvested plant from attack or infestation by nematode pests or parasites which comprises applying to the foliage of said plant or to the soil or water in which it is growing a pesticidally effective amount of a compound of formula I according to claim 1; or a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof.
 12. The compound according to claim 1 wherein R₂ is 4-(4-F-phenyl)-pyridin-3-yl, 4-(4-OCF3-phenyl)-pyridin-3-yl, 4-(4-Cl-phenyl)-pyridin-3-yl or 4-(3-Cl-phenyl)-pyridin-3-yl.
 13. The compound according to claim 12 wherein R₁ is 4-CN—C₆H₄.
 14. The compound according to claim 1 wherein R₁ is 4-CN—C₆H₄.
 15. The compound according to claim 12 wherein R₁ is 4-OCF3-C₆H₄.
 16. The compound according to claim 1 wherein R₁ is 4-OCF₃—C₆H₄. 